Adenovirus with modified binding moiety specific for the target

Details Adenovirus with modified binding moiety specific for the target Adenovirus with modified binding moiety specific for the target

1995-07-05

1999-03-23

Railey, II, Johnny F.

Chemistry: molecular biology and microbiology

Treatment of micro-organisms or enzymes with electrical or...

Modification of viruses

424 932, 4353201, 536 231, 536 234, 536 2372, C12N 1586, C12N 1534, A61K 39235

Patent

active

058858083

DESCRIPTION:

BRIEF SUMMARY
This Application is the national stage filing under 35 U.S.C. 371 of PCT/GB93/02267, which was filed on Nov. 4, 1993, published as WO94/10323 May 11, 1994.
The present invention relates to delivery vehicles for genes to target cells, especially in the fields of gene therapy and cancer treatment.
The delivery of genes to target cells, especially those within the mammalian body, has many uses, for example in the fields of gene therapy, cancer treatment and in areas of genetic manipulation still to be discovered. The gene to be delivered may encode a molecule, such as a protein or RNA, which is cytotoxic to the target cell, or it may encode a functional copy of a gene that is defective in the target cell. In this latter case the product of the aforementioned functional copy of the gene will replace that of the defective copy, and the target cell will be able to perform its proper function.
The use of viruses, or virus-like particles, to deliver genes for gene therapy and cancer treatment has been disclosed.
However, in most cases the targeting of the virus or virus-like particles containing the desired gene to the cell has relied on the natural host-virus specificity or on local application of the virus to the cells to be targeted, for example direct application of viruses to lung cells by inhalation.
The human adenovirus 5 (Ad5) genome consists of a double-stranded linear DNA molecule of 36 kilo-basepair. The virus replication cycle has two phases: an early phase, during which four transcriptional units E1, E2, E3, and E4 are expressed, and a late phase occurring after the onset of viral DNA synthesis when late transcripts are expressed from the major late promoter (MLP). These late messages encode most of the viral structural proteins. E1, E2, and E4 gene products of human adenoviruses (Ads) are involved in transcriptional activation, cell transformation, and viral DNA replication as well as other viral functions, and are essential for viral growth. In contrast, E3 gene products are not required for viral replication in cultured cells or for acute lung infection of cotton rats, but appear to be involved in evading immune surveillance in vivo.
By "virus-like particle" we mean a nucleoprotein particle containing a core of nucleic acid surrounded by protein which (i) is not infective and (ii) can only be propagated in a suitable cell system following transformation by its nucleic acid. Thus a virus-like particle of mammalian origin may be propagated in Saccharomyces cerevisiae or in insect cells via a baculovirus expression system.
The modification of coat proteins of filamentous bacteriophages (bacterial viruses), such as M13 and fd, so as to generate novel binding properties, has been disclosed in Cwirla et al (1990) Proc. Natl. Acad. Sci. USA 87, 6378-6382 and Scott & Smith (1990) Science 249, 386-390.
It has previously been suggested that retroelement particles, including retroviral vectors, may be modified to target specific cells, for example see Kingsman et al (1991) Tibtech 9, 303-309.
Russell et al (1993) Nucl. Acids Res. 21, 1081-1085, published after the priority date for this application but before the filing date discloses retroviral vectors displaying functional antibody fragments and suggests that, in principle, the display of antibody fragments on the surface of recombinant retroviral particles could be used to target virus to cells for gene delivery. However, it is not known whether a retrovirus can be assembled in which all the subunits of the viral envelope protein are fused to antibody, and if so whether the virus would infect cells. NIP-derivatised human cells were tested as a method for targeted gene delivery, but became permissive for both modified (displaying an anti-NIP antibody) and unmodified ecotropic viral particles. NIP is 4hydroxy-3-iodo-5-nitrophenylacetic acid.
Michael et al (1993) J. Biol. Chem. 268, 6866-6869, published after the priority date of this application but before the filing date, describes molecular conjugates between adenovirus and a vector system comprising two l

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