Viral vectors having chimeric envelope proteins containing the IgG-binding domain of protein A

a technology of chimeric envelope proteins and viral vectors, applied in the field of viral vectors, can solve the problems of limited application of this approach, no practical general, and possible recombination between the two

Inactive Publication Date: 2003-03-13
NEW YORK UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Secondly, there are well developed techniques to produce a stock of infectious vector particles that do not cause the production of viral particles in the transduced target cell.
One disadvantage of the use of retroviral vectors is that there is presently no practical general, method whereby a particular tissue or cell type of interest can be specifically transduced.
The technical difficulties of the ex vivo culture technique combined with the unavailability of growth factors of specific for some types of cells have limited the application of this approach.
A second difficulty presented by the use retroviral based vectors is that a recombination may occur between sequences of vector and an endogenous retrovirus.
Because of their ability to infect such a broad spectrum of cells, a major drawback to the use of amphotropic virus vectors is the fact that these vectors lack target-cell specificity.
However, this type of approach suffers from at least two limitations.
Second, virions constructed to directly bind to specific targets in human cells are intrinsically unsafe, as wild-type recombinants could produce potentially harmful effects patients treated with such vectors.
The method of Neda results in a variable number of binding sites for the exposed acceptor on the target cell, attached to each derivatized or bound envelope protein and, of course, is limited to the case wherein the target cell has a lactose receptor.
However, a major drawback to the use of Sindbis virus vectors is the fact that these vectors lack target-cell specificity.

Method used

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  • Viral vectors having chimeric envelope proteins containing the IgG-binding domain of protein A
  • Viral vectors having chimeric envelope proteins containing the IgG-binding domain of protein A
  • Viral vectors having chimeric envelope proteins containing the IgG-binding domain of protein A

Examples

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example 1

6.1. Example 1

[0040] In this example we describe the construction of a recombinant ecotropic retrovirus displaying protein A-envelope chimeric proteins. Protein A, a protein derived from Staphylococcus aureus, has a strong affinity for the Fc region of various mammalian IgGs (Surolia, A. et al., 1982, Trends Biochem. Sci. 7:74-76). Native protein A has five homologous IgG-binding domains (E, D, A, B and C), and we have utilized the synthetic Z domain which is based on the B domain of protein A (Nilsson, B. et al., 1987, Protein Eng. 1:107-113). The development of retroviral vectors that can bind IgGs (monoclonal antibodies) would have important applications for specific gene delivery.

[0041] Materials and Methods

[0042] 6.1.1. Plasmids and Cell Line.

[0043] A SV40-based plasmid, p439 (SV-E-MLV-env), which express Moloney MLV (Mo-MLV) envelope protein (Landau, N. R. et al., 1992, J. Virol. 66:5110-5113), was kindly provided Dr. Dan R. Littman, New York University. pEZZ 18, which contain...

example 2

6.2. Example 2

[0061] In this example we describe the construction of a recombinant Sindbis virus vector displaying protein A-envelope chimeric proteins to redirect the viral tropism. Protein A (PA), a protein derived from Staphylococcus aureus, has a strong affinity for the Fc region of various mammalian IgGs (Surolia, A. et al., 1982). In contrast to the targeted retroviral vectors described above, the PA-envelope chimeric virus vector once successfully generated needs no further modification to target distinct cells. The targeting is achieved simply by changing the complementary mAb (FIG. 3A). More importantly, we demonstrate that this chimeric virus used in conjunction with mAbs can infect human cells and transfer a test gene, bacterial .beta.-galactosidase with high efficiency. The novel cell targeting system which utilizes PA-mAb interaction for virus infection would have important applications for gene expression studies and therapy.

[0062] 6.2.1. Results

[0063] 6.2.2. Construct...

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Abstract

The invention involves viral vectors that can be used to tranduce a target cell, i.e. to introduce genetic material into the cell. The targets of interest are eukaryotic cells and particularly human cells. The transduction can be done in vivo or in vitro. More particularly the invention concerns viral vectors that have chimeric envelope proteins and contain the IgG-binding domain of protein A. These vectors when used in conjunction with antibodies targeting a particular cell are particularly useful for gene therapy.

Description

1. FIELD OF THE INVENTION[0001] The invention involves viral vectors that can be used to transduce a target cell, i.e., to introduce genetic material into the cell. The targets of interest are eukaryotic cells and particularly human cells. The transduction can be done in vivo or in vitro. More particularly the invention concerns viral vectors that have chimeric envelope proteins and contain the IgG-binding domain of protein A. These vectors when used in conjunction with antibodies targeting a particular cell are particularly useful for gene therapy.2. BACKGROUND OF THE INVENTION[0002] A variety of viral based vectors have been employed to transfer and to express a gene of interest into a eukaryotic target cell. Recombinant DNA techniques are used to replace one or more of the genes of the virus with the gene of interest operably linked to a promoter that is functional in the target cell. The construct, termed a viral vector, infects the target cell, using the physiological infective...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K48/00C07K14/15C07K19/00C12N5/10C12N7/00C12N15/09C12N15/13C12N15/86
CPCC12N2810/6018C12N2810/609A61K48/00C07K14/005C12N7/00C12N15/86C12N2740/13022C12N2770/36122C12N2770/36143C12N2770/36145C12N2770/36152
Inventor MERUELO, DANIELOHNO, KOUICHI
Owner NEW YORK UNIV
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