Integrin-targeted imaging and therapy with RGD4C-TNF fusion protein

Wang, Hui; Chen, Kai; Cai, Weibo; Li, Zibo; He, Lina; Kashefi, Amir; Chen, Xiaoyuan

doi:10.1158/1535-7163.mct-07-2084

Cited by 47 publications

(38 citation statements)

References 30 publications

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“…Recently, RGD and other targeted motifs have been used for tumor-targeted delivery of recombinant TNF-a. [28][29][30][31] Among these, NGR-TNF, an aminopeptidase N (CD13) ligand that targets activated blood vessels in tumors, looks very promising. In this molecule, TNF-a is fused with the C terminus of CNGRCG peptide.…”

Section: Discussionmentioning

confidence: 99%

Tumor vasculature‐targeted delivery of tumor necrosis factor‐α*

Tandle

Hanna

Lorang

et al. 2008

Cancer

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BACKGROUND: Recently, considerable efforts have been directed toward antivascular therapy as a new modality to treat human cancers. However, targeting a therapeutic gene of interest to the tumor vasculature with minimal toxicity to other tissues remains the objective of antivascular gene therapy. Tumor necrosis factor‐α (TNF‐α) is a potent antivascular agent but has limited clinical utility because of significant systemic toxicity. At the maximum tolerated doses of systemic TNF‐α, there is no meaningful antitumor activity. Hence, the objective of this study was to deliver TNF‐α targeted to tumor vasculature by systemic delivery to examine its antitumor activity. METHODS: A hybrid adeno‐associated virus phage vector (AAVP) was used that targets tumor endothelium to express TNF‐α (AAVP‐TNF‐α). The activity of AAVP‐TNF‐α was analyzed in various in vitro and in vivo settings using a human melanoma tumor model. RESULTS: In vitro, AAVP‐TNF‐α infection of human melanoma cells resulted in high levels of TNF‐α expression. Systemic administration of targeted AAVP‐TNF‐α to melanoma xenografts in mice produced the specific delivery of virus to tumor vasculature. In contrast, the nontargeted vector did not target to tumor vasculature. Targeted AAVP delivery resulted in expression of TNF‐α, induction of apoptosis in tumor vessels, and significant inhibition of tumor growth. No systemic toxicity to normal organs was observed. CONCLUSIONS: Targeted AAVP vectors can be used to deliver TNF‐α specifically to tumor vasculature, potentially reducing its systemic toxicity. Because TNF‐α is a promising antivascular agent that currently is limited by its toxicity, the current results suggest the potential for clinical translation of this strategy. Cancer 2009. Published 2008 by the American Cancer Society.

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Section: Discussionmentioning

confidence: 99%

Tumor vasculature‐targeted delivery of tumor necrosis factor‐α*

Tandle

Hanna

Lorang

et al. 2008

Cancer

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“…In the treated mice, an increase of fractional tumor volume from day 14 (V/V 0 5 0.51) to day 21 (V/V 0 5 0.65) was noted. This pattern of initial response during and immediately after the treatment, and then regrowth after the treatment was stopped, is common in many other experimental cancer therapy studies and clinical cancer trials (25)(26)(27). Mouse body weight was monitored as an indicator of the toxicity of Abraxane.…”

Section: Abraxane Treatment-inhibited Mda-mb-435 Tumor Growthmentioning

confidence: 97%

¹⁸F-FPPRGD2 and ¹⁸F-FDG PET of Response to Abraxane Therapy

Sun¹,

Yan²,

Liu³

et al. 2010

J Nucl Med

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“…Designing a clinically relevant TNF-α mutant with low systemic toxicity and high anti-tumor activity has been of intense pharmacological interest in the past two decades[20–25]. Human TNF-α, which binds to the murine TNF receptor 55 (TNF-R55, 55kDa) but not to the murine TNF receptor 75 (TNF-R75, 75kDa) exhibits retained antitumor activity and reduced systemic toxicity in mice compared to that of murine TNF-α, which binds to both murine TNF receptors[27,28].…”

Section: Discussionmentioning

confidence: 99%

“…Various strategies, such as small molecule IAP (inhibitor of apoptosis) antagonists synergism, prodrugs and local application (isolated limb or hepatic perfusion), have been pursued to minimize the systemic toxicities of TNF-α, to increase TNF-α sensitivity and availability in tumor cells, and therefore to increase the therapeutic index[16–20]. A promising approach to achieve these aims is to design clinically applicable TNF-α mutants with low systemic toxicity and high efficiency and it has been of great interest[21–25].…”

Section: Introductionmentioning

confidence: 99%

Safety evaluation and pharmacokinetics of a novel human tumor necrosis factor-alpha exhibited a higher antitumor activity and a lower systemic toxicity

Li¹,

Qin

Xue

et al. 2010

Anti-Cancer Drugs

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We have previously prepared a prokaryotic expressed TNF-α mutant which exhibited a higher anti-tumor activity and a lower systemic toxicity compared with that of wild type TNF-α in both syngeneic murine tumor models and human tumor xenografts models. For its clinical use as an anti-tumor agent, we evaluate repeated dose toxicity, anaphylaxis, genetic toxicity, pharmacokinetic and metabolism in different animals according to the criteria for biological Investigational New Drug (IND) application. It was found to be safe at a dose of 4×106 IU/kg/day for 60 days after administration in rhesus monkeys but the TNF-α antibody level and liver toxicity needed to be monitored. No systemic anaphylaxis or genetic toxicity were found and the pharmacokinetic characteristics of the rmhTNF-α were suited for clinical use. Over 96.3% of rmhTNF-α could be reclaimed from the urine and feces in 24 hours after administration, which indicated the main excretion route. The results proved the characteristics of this rmhTNF-α satisfied clinical trial requirements. The related positive clinical trial results will be reported in future. This study of novel rmhTNF-α is of considerable importance, not only given the proven usefulness of TNF-α local application therapies under ILP (Isolated Limp Perfusion) and IHP (Isolated Hepatic Perfusion) conditions for selected indications, but also implicated for systemic application of TNF-α.

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Integrin-targeted imaging and therapy with RGD4C-TNF fusion protein

Abstract: This study used integrin A v

Cited by 47 publications

References 30 publications

Tumor vasculature‐targeted delivery of tumor necrosis factor‐α*

Tumor vasculature‐targeted delivery of tumor necrosis factor‐α*

¹⁸F-FPPRGD2 and ¹⁸F-FDG PET of Response to Abraxane Therapy

Safety evaluation and pharmacokinetics of a novel human tumor necrosis factor-alpha exhibited a higher antitumor activity and a lower systemic toxicity

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Integrin-targeted imaging and therapy with RGD4C-TNF fusion protein

Abstract: This study used integrin A v

Cited by 47 publications

References 30 publications

Tumor vasculature‐targeted delivery of tumor necrosis factor‐α*

Tumor vasculature‐targeted delivery of tumor necrosis factor‐α*

18F-FPPRGD2 and 18F-FDG PET of Response to Abraxane Therapy

Safety evaluation and pharmacokinetics of a novel human tumor necrosis factor-alpha exhibited a higher antitumor activity and a lower systemic toxicity

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¹⁸F-FPPRGD2 and ¹⁸F-FDG PET of Response to Abraxane Therapy