Targeted gene delivery to mammalian cells by filamentous bacteriophage

Poul, Marie‐Alix; Marks, James D.

doi:10.1006/jmbi.1999.2678

Cited by 138 publications

(84 citation statements)

References 31 publications

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“…12,24 Bacteriophage that carries an antibody directed to the cell surface receptor ErbB2 can infect and express a transgene in receptor-positive cells. 25 However, the transduction efficiency for these vectors is very low (%1%-9%), although multivalent phagemid particles have been used. 12,16,25,26 Thus, the use of a native, singlestrand bacteriophage has very limited clinical utility as a therapeutic agent.…”

Section: Discussionmentioning

confidence: 99%

“…25 However, the transduction efficiency for these vectors is very low (%1%-9%), although multivalent phagemid particles have been used. 12,16,25,26 Thus, the use of a native, singlestrand bacteriophage has very limited clinical utility as a therapeutic agent. In contrast, the use of targeted AAVP in our study was able to circumvent this problem, because AAVP-transduced cells generate functional AAV particles with reasonable transduction efficiency.…”

Section: Discussionmentioning

confidence: 99%

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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%

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 a receptor-dependent manner (27), and panning was carried out at 37°C, it is possible that the capacity of some of the phage clones to induce their own endocytosis may have played a role in the selection process. The proteins encoded by these phage might then have improved antiviral activity owing to an increased capacity to induce CCR5 sequestration, as has been previously shown for a number of N-terminally modified chemokines with enhanced anti-HIV activity (7,18,31,36).…”

Section: Mechanism Underlying Improved Anti-hiv Activity (I)mentioning

confidence: 99%

Human Immunodeficiency Virus Type 1 Entry Inhibitors Selected on Living Cells from a Library of Phage Chemokines

Hartley

Dorgham

Perez-Bercoff

et al. 2003

J Virol

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The chemokine receptors CCR5 and CXCR4 are promising non-virus-encoded targets for human immunodeficiency virus (HIV) therapy. We describe a selection procedure to isolate mutant forms of RANTES (CCL5) with antiviral activity considerably in excess of that of the native chemokine. The phage-displayed library of randomly mutated and N-terminally extended variants was screened by using live CCR5-expressing cells, and two of the selected mutants, P1 and P2, were further characterized. Both were significantly more potent HIV inhibitors than RANTES, with P2 being the most active (50% inhibitory concentration of 600 pM in a viral coat-mediated cell fusion assay, complete protection of target cells against primary HIV type 1 strains at a concentration of 10 nM). P2 resembles AOP-RANTES in that it is a superagonist of CCR5 and potently induces receptor sequestration. P1, while less potent than P2, has the advantage of significantly reduced signaling activity via CCR5 (30% of that of RANTES). Additionally, both P1 and P2 exhibit not only significantly increased affinity for CCR5 but also enhanced receptor selectivity, retaining only trace levels of signaling activity via CCR1 and CCR3. The phage chemokine approach that was successfully applied here could be adapted to other chemokine-chemokine receptor systems and used to further improve the first-generation mutants reported in this paper.Despite the success of highly active antiretroviral therapy, new human immunodeficiency virus type 1 (HIV-1) inhibitors are still needed and among the most promising new approaches is the blockade of viral entry into target cells (20). HIV-1 entry into target cells is initially dependent on the interaction of its envelope glycoproteins with CD4 and a coreceptor, with the chemokine receptors CCR5 and CXCR4 being by far the most commonly used by HIV-1 (5).HIV entry is inhibited by the natural chemokine ligands of the coreceptors, including MIP-1␣ (CCL3), MIP-1␤ (CCL4), and RANTES (CCL5) for CCR5 (8) and SDF-1 (CXCL12) for CXCR4 (6,23). Certain N-terminal modifications have been shown to increase the anti-HIV activity of native chemokines (21,32,33,36), and the most potent of these molecules owe their anti-HIV activity to their ability to induce prolonged intracellular sequestration of coreceptors (18,31).Up until now, chemokine structure-activity relationships have been studied via either scanning or truncation mutagenesis (14,16,19,24), peptide scanning of primary sequence (22), or semirational design of chemokine analogues (21,32,36). A more-rapid, bioengineering-based approach for the selection of useful chemokine variants has yet to be described.We decided to apply current knowledge of the structureactivity relationship of chemokines and the mechanism by which they inhibit HIV entry (2,7,18) to the design of a phage display strategy for the discovery of N-terminally mutated RANTES variants with improved anti-HIV activity. Selection led to the isolation of around 40 clones that exhibited a consensus sequence, and two clones were chosen...

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“…[ 18 F]FEAU has also been used to monitor the response of tumors using PETafter systemic Sindbis/tk (vector) treatment as a basis for determining the levels of tissue distribution of vectors in living animals 26 . Bacteriophages (phages) are bacterial viruses that can be adapted to transduce mammalian cells by targeting to a specific receptor [27][28][29][30][31][32] . We have recently developed and evaluated a novel phage-based targeted vector, a genetic chimera of filamentous phage and recombinant AAV (termed AAVP) 28 .…”

Section: Introductionmentioning

confidence: 99%