Preclinical safety evaluation of IFNα2a-NGR

Meng, Jing; Zhang, Yan; Wu, Yongjie; Gao, Ming-Tang; Li, Wenguang; Gao, Fei; Wang, Hongxing; Han, Wei; Zhang, Yingqi

doi:10.1016/j.yrtph.2007.10.014

Cited by 10 publications

(6 citation statements)

References 24 publications

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“…and was purified by ion exchange chromatography. The preclinical safety evaluation of IFN-α2a-NGR showed that administration of this recombinant protein was extremely well tolerated with very high doses in mice, rats and monkeys (Meng et al 2008 ). In the current study, we confirmed the tumor inhibition effect of IFN-α2a-NGR in vivo and found that it was 3× more potent than IFN-α2a in elicting its anti-tumor effects in A549- and SPC-A-1- bearing mice.…”

Section: Discussionmentioning

confidence: 99%

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Recombinant IFN-α2a-NGR exhibits higher inhibitory function on tumor neovessels formation compared with IFN-α2a in vivo and in vitro

Hao

et al. 2014

Cytotechnology

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We previously reported that NGR-fused IFN-α2a (IFN-α2a-NGR) exhibited similar biological activities with native IFN-α2a and was well-tolerated in mice, rats and monkeys. In the current study, we evaluated the mechanisms of this fusion protein on angiogenesis and tumor formation. Our data indicated that IFN-α2a-NGR has the ability to target tumor blood vessels while preserving the original function of native IFN-α2a. IFN-α2a-NGR was found to be concentrated in the tumor tissues, particularly around the vessel areas. In contrast to IFN-α2a, IFN-α2a-NGR significantly decreased microvessel density and increased the apoptosis of vascular endothelial cells. IFN-α2a-NGR also decreased the expression of VEGF and bFGF in tumor cells. Significant inhibition of invasion, migration, tube formation and induction of apoptosis of endothelial cells were observed in IFN-α2a-NGR-treated group. In conclusion, results from in vitro and in vivo experiments indicate that IFN-α2a-NGR is a promising anti-angiogenic agent with greater therapeutic efficacy than IFN-α2a.Electronic supplementary materialThe online version of this article (doi:10.1007/s10616-014-9743-y) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

“…Purification was achieved via ion exchange chromatography (Meng et al 2007 ). Preclinical safety studies revealed that IFN-α2a-NGR was well tolerated at pharmacologically active doses in mice, rats and monkeys (Meng et al 2008 ).…”

Section: Introductionmentioning

confidence: 99%

Recombinant IFN-α2a-NGR exhibits higher inhibitory function on tumor neovessels formation compared with IFN-α2a in vivo and in vitro

Hao

et al. 2014

Cytotechnology

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“…Again, these results further supported previous works demonstrating the good tolerability of interferon. Thus, Meng et al [15] showed that after repeated dose of IFNalpha-2a-NGR (Asn-Gly-Arg), all the clinical chemistry changes were of minor severity there were no pertinent abnormal parameters or results observed [15]. Furthermore, these authors found that the increase in spleen and thymus organ-to-body weight ratios and decrease in menses were mild, reversible, and likely related to the pharmacology of the interferon.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Adverse Effects of Mutein Forms of Recombinant Human Interferon Alpha-2b in Female Swiss Webster Mice

Rachmawati

Merika

Ningrum

et al. 2013

BioMed Research International

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Purpose. We successfully developed recombinant human interferon alpha-2b (rhIFN-α2b) and mutein forms through the site-directed mutagenesis technique. The mutein forms were developed by substituting cysteins at positions 2 and 99 with aspartic acids. The potential adverse effects of these rhIFN-α2bs were assessed by acute and subchronic studies. Methods. In the acute study, rhIFN-α2bs were subcutaneously administered to mice at a single dose of 97.5 μg/kg, 975 μg/kg, and 9.75 mg/kg BW and were observed for 14 days. In the subchronic study, single dose of 1.95 μg/kg and 19.5 μg/kg, respectively, was given subcutaneously every 3 days for 45 days. Results. No death as well as abnormality in body weight, behavior, presentation of main organs, and value of plasma SGPT and SGOT was observed. Wild type and mutein rhIFN-α2bs did not show significant adverse effects at dose up to 9.75 mg/kg BW. Administration of these rhIFN-α2bs given repeatedly did not induce any adverse effect. Conclusion. These results suggest that our rhIFN-α2bs are safe. However, further study is still needed to clarify the safety issue before use in clinical trial.

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“…Other investigators showed that the anti-tumor activity of IFNα2a can also be increased by coupling this protein with an NGR peptide [ 85 ]. Studies performed in animal models showed that the IFNα2a-NGR conjugate, but not IFNα2a, accumulates and target tumor vessels [ 86 – 88 ].…”

Section: The Ngr-mediated Targeting Of Cytokines To Tumor Vasculaturementioning

confidence: 99%

Peptide-Mediated Targeting of Cytokines to Tumor Vasculature: The NGR-hTNF Example

et al. 2013

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A growing body of evidence suggests that the efficacy of cytokines in cancer therapy can be increased by targeting strategies based on conjugation with ligands that recognize receptors expressed by tumor cells or elements of the tumor microenvironment, including the tumor vasculature. The targeting approach is generally conceived to permit administration of low, yet pharmacologically active, doses of drugs, thereby avoiding toxic reactions. However, it is becoming clear that, in the case of cytokines, this strategy has another inherent advantage, i.e. the possibility of administering extremely low doses that do not activate systemic counter-regulatory mechanisms, which may limit their potential therapeutic effects. This review is focused on the use of tumor vasculature-homing peptides as vehicles for targeted delivery of cytokines to tumor blood vessel. In particular, we provide an overview of peptide-cytokine conjugates made with peptides containing the NGR, RGD, isoDGR or RGR sequences and describe, in more details, the biological and pharmacological properties of NGR-hTNF, a peptide-tumor necrosis factor-α conjugate that is currently being tested in phase II and III clinical studies. The results of preclinical and clinical studies performed with these products suggest that peptide-mediated vascular-targeting is indeed a viable strategy for delivering bioactive amounts of cytokines to tumor endothelial cells without causing the activation of counter-regulatory mechanisms and toxic reactions.

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Preclinical safety evaluation of IFNα2a-NGR

Cited by 10 publications

References 24 publications

Recombinant IFN-α2a-NGR exhibits higher inhibitory function on tumor neovessels formation compared with IFN-α2a in vivo and in vitro

Recombinant IFN-α2a-NGR exhibits higher inhibitory function on tumor neovessels formation compared with IFN-α2a in vivo and in vitro

Evaluation of Adverse Effects of Mutein Forms of Recombinant Human Interferon Alpha-2b in Female Swiss Webster Mice

Peptide-Mediated Targeting of Cytokines to Tumor Vasculature: The NGR-hTNF Example

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