Generation of a novel long-acting thymosin alpha1-Fc fusion protein and its efficacy for the inhibition of breast cancer in vivo

Shen, Xutong; Li, Qingqing; Wang, Fanwen; Bao, Jingxiao; Dai, Mengting; Zheng, Heng; Lao, Xingzhen

doi:10.1016/j.biopha.2018.09.064

Cited by 6 publications

(7 citation statements)

References 55 publications

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“…Furthermore, the C-terminally attached PAS moiety was compatible with N-terminal acetylation by RimJ as confirmed by ESI-MS. Yields of our expression study at the research scale reached 15 mg purified acetylated Tα1-PAS and even 50 mg PAS-Tα1 per 1 L bacterial culture (at an optical density (OD) of 3), which surpasses the reported yield of a bacterially produced (yet probably non-acetylated and non-glycosylated) Tα1-Fc fusion protein (16 mg/L) [44].…”

Section: Discussionmentioning

confidence: 64%

“…While attachment of large macromolecules, such as PAS polypeptides or albumin, but also PEG [53], can lead to lower receptor association rates for bioactive peptides or proteins, this is usually overcompensated by the drastically prolonged in vivo half-life, which results in a strongly enhanced bioactivity as demonstrated for multiple PASylated biopharmaceuticals [37,54]. In the case of Tα1, superior effects in preclinical cancer models due to prolonged circulation were recently demonstrated for a Tα1-Fc fusion protein [41,44]. Such studies would be the obvious next step to investigate enhanced in vivo bioactivity of PASylated Tα1, and it will be interesting to see whether its N-terminally or C-terminally PASylated version performs better.…”

Section: Discussionmentioning

confidence: 99%

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PASylated Thymosin α1: A Long-Acting Immunostimulatory Peptide for Applications in Oncology and Virology

Binder¹,

Skerra

2020

IJMS

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Thymosin α1 (Tα1) is an immunostimulatory peptide for the treatment of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections and used as an immune enhancer, which also offers prospects in the context of COVID-19 infections and cancer. Manufacturing of this N-terminally acetylated 28-residue peptide is demanding, and its short plasma half-life limits in vivo efficacy and requires frequent dosing. Here, we combined the PASylation technology with enzymatic in situ N-acetylation by RimJ to produce a long-acting version of Tα1 in Escherichia coli at high yield. ESI-MS analysis of the purified fusion protein indicated the expected composition without any signs of proteolysis. SEC analysis revealed a 10-fold expanded hydrodynamic volume resulting from the fusion with a conformationally disordered Pro/Ala/Ser (PAS) polypeptide of 600 residues. This size effect led to a plasma half-life in rats extended by more than a factor 8 compared to the original synthetic peptide due to retarded kidney filtration. Our study provides the basis for therapeutic development of a next generation thymosin α1 with prolonged circulation. Generally, the strategy of producing an N-terminally protected PASylated peptide solves three major problems of peptide drugs: (i) instability in the expression host, (ii) rapid degradation by serum exopeptidases, and (iii) low bioactivity because of fast renal clearance.

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

PASylated Thymosin α1: A Long-Acting Immunostimulatory Peptide for Applications in Oncology and Virology

Binder¹,

Skerra

2020

IJMS

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“…Elsewhere, Moody et al demonstrated that in Fischer rats 10 μg daily injections of Thα1 decreased the occurrence of mammary carcinoma and treated animals with Thα1 enhanced the number of blood white cell compared to fisher rats control . Two studies have shown that the conjugation of Thα1 to the Fc domain of human IgG4 increased the half‐life and antitumor activity of Thα1 in 4T1 and breast cancer . Also, Wang et al found that Thα1‐Fc improved the antitumor activity in 4T1 and B16F10 tumor models through upregulating CD86 expression, secreting IFN‐γ and IL‐2, and enhancing the number of tumor‐infiltrating CD4+ T and CD8+ T cells .…”

Section: Discussionmentioning

confidence: 99%

Thymosin alpha‐1; a natural peptide inhibits cellular proliferation, cell migration, the level of reactive oxygen species and promotes the activity of antioxidant enzymes in human lung epithelial adenocarcinoma cell line (A549)

Kharazmi-Khorassani

Asoodeh

2019

Environmental Toxicology

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This research was conducted to investigate the biochemical effects of thymosin alpha-1 using human lung cancer cells (A549). The A549 cells were treated with different concentrations of Thα1 for 24 h and the growth, inhibition of cells was determined. Thα1 revealed anti-proliferative effect at 24 and 48 μg/ml after 24 h. Furthermore, it indicated antioxidant properties by significantly enhancing the activity of catalase (12 μg/ml), superoxide dismutase (6 and 12 μg/ml), and glutathione peroxidase (3, 6 and 12 μg/ml) and reducing the production of cellular ROS. Our results showed that Thα1 inhibits the migration of A549 cells in a concentration-dependent manner after 24 and 48 h. Moreover, the effect of Thα1 on apoptosis was investigated by Hoechst 33342 staining and cell cycle analysis. Results demonstrated no significant effect on the induction of apoptosis in A549 cells. In conclusion, our results showed the antioxidant properties of Thα1 on A549 cancer cells. K E Y W O R D S antioxidant enzyme, cytotoxicity, reactive oxygen species, thymosin alpha-1

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“…However, Tα1 has antitumor activity; when it acts on tumor cells, it also acts on normal cells and causes a series of side effects, thus limiting its clinical use. In previous studies, Tα1-modified peptides or Tα1 in combination with other drugs have shown better antitumor activity than Tα1 alone. , RGD (Arg-Gly-Asp) and iRGD (CRGDKGPDC) have been utilized in delivering a limited number of anticancer drugs to tumor sites to increase the effects of anticancer drugs. To deliver Tα1 more efficiently to tumor tissues, we designed a new peptide, Tα1-RGDR .…”

Section: Introductionmentioning

confidence: 99%

“…In previous studies, Tα1modified peptides or Tα1 in combination with other drugs have shown better antitumor activity than Tα1 alone. 21,22 RGD (Arg-Gly-Asp) 23 and iRGD (CRGDKGPDC) 22 new peptide, Tα1-RGDR. 24 RGDR contains an RGD sequence that can bind to integrin αvβ3, which is overexpressed in many tumor surfaces.…”

Section: ■ Introductionmentioning

confidence: 99%

Modified Thymosin Alpha 1 Distributes and Inhibits the Growth of Lung Cancer in Vivo

Peng

Zheng

et al. 2020

ACS Omega

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Targeted therapy of tumors is an effective method for treating cancer. Thymosin alpha 1 (Tα1), a hormone that contains 28 amino acids, is already approved for cancer treatment. However, its clinical application is limited because of the lack of tumor targeting. Considering that RGD can specifically bind to integrin, the anticancer drug can have a targeted therapeutic effect on tumors when it combines with a peptide containing an RGD sequence. We produced a polypeptide, Tα1-RGDR, by binding Tα1 to RGDR. The RGDR can combine with the αvβ3 and NRP-1 domains, which are highly expressed on the surface of the tumor, to achieve the effect of tumor targeting. This work aimed to investigate the difference of antitumor activity and tumor targeting between Tα1 modified by RGDR and Tα1 by using H460 and LLC tumor models. Results showed that Tα1-RGDR had remarkable antitumor effects, and its tumor targeting was better than that of Tα1. Hence, Tα1-RGDR is a promising antitumor drug.

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Generation of a novel long-acting thymosin alpha1-Fc fusion protein and its efficacy for the inhibition of breast cancer in vivo

Cited by 6 publications

References 55 publications

PASylated Thymosin α1: A Long-Acting Immunostimulatory Peptide for Applications in Oncology and Virology

PASylated Thymosin α1: A Long-Acting Immunostimulatory Peptide for Applications in Oncology and Virology

Thymosin alpha‐1; a natural peptide inhibits cellular proliferation, cell migration, the level of reactive oxygen species and promotes the activity of antioxidant enzymes in human lung epithelial adenocarcinoma cell line (A549)

Modified Thymosin Alpha 1 Distributes and Inhibits the Growth of Lung Cancer in Vivo

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