Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Virus or component thereof
Patent
1997-10-08
2000-10-17
Bui, Phuong T.
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Virus or component thereof
4241991, 424 931, 4241871, 4241921, 4352351, 435325, 435357, 435 5, 4353201, 514 44, 530350, 530300, 53038835, 536 231, 536 234, 536 2372, C07H 2102, C07K 1415, C12N 701
Patent
active
06132731&
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to a proteinaceous particle comprising a capsid, optionally containing nucleic acid, the capsid being enveloped by proteins adapted to target and deliver the particle to a desired host cell. Methods and materials for the preparation of such particles, and pharmaceutical compositions containing them, are also part of the invention. Such particles find application in immunology and gene delivery (gene therapy).
BACKGROUND OF THE INVENTION
Proteinaceous particles of the same order of magnitude as virions, which have affinity for particular cell types are potentially useful as delivery vehicles for bringing a desired therapeutic molecule carried by the particles into contact with cells of that type. The therapeutic molecule may be, for example, an antigen capable of stimulating a target cell of the immune system, or nucleic acid for incorporation within the target cell, the latter objective being a minimum requirement for successful gene therapy applications.
The use of recombinant retroviruses as vehicles in gene therapy is gaining increasing support. Natural retroviruses comprise a GAG protein "core" or "capsid", these terms being used interchangeably, the capsid being enveloped by the envelope proteins (strictly these are glycoproteins but will be referred to herein simply as envelope proteins), and within the capsid is packaged the viral genomic RNA. By application of recombinant nucleic acid technology, the structure of the capsid and envelope proteins, and of the genomic RNA, of a natural retrovirus may be altered. Thus, recombinant particles comprising capsid and envelope proteins can be used to carry foreign nucleic acid, for insertion into cells which are members of the host range defined by the receptor binding specificity of the envelope proteins. A major goal in retroviral gene therapy is to alter the host range of recombinant retroviral particles to target the particles to particular cell types and to provide efficient transduction. The preferred virus for developing retroviral gene therapy is generally accepted to be murine leukemia virus (MLV).
Outside the specific area of gene therapy, it would also be desirable to adapt proteinaceous particles for targeting to specific cell types, for example to deliver specific antigens to target cells of the immune system by presenting such antigens on proteinaceous virion-like particles whose envelope proteins carry sequences having an affinity for the desired target cell type.
Specific interactions have been proposed between the transmembrane (TM) domain of envelope (ENV) proteins and the matrix (MA) domain of GAG protein for selective incorporation of the envelope proteins into the self-assembling particle. In addition, the cell receptor binding domain of retroviral envelope proteins has been located near the N-terminus. In MLV, two discontinuous receptor recognition regions termed VRA and VRB have been identified (Battini et al. (1992) J. Virol. 66:1468-1475)). Any modification of the envelope protein to confer specific cell targeting properties on an enveloped capsid must retain the regions important for incorporation of the envelope, yet possess an altered receptor binding domain for targeted infection.
The use of targeted retroviral particles as carriers has been attempted before. Young et al. (1990) attempted to selectively incorporate CD4 into ALV particles by fusing CD4 to a truncated viral envelope protein. Curiously, there was incorporation of wild-type CD4 but very poor incorporation of the fusion protein. The absolute efficiency of incorporation was difficult to determine, and it is possible that both wild-type and fusion CD4 were poorly picked up by the virus.
In WO 94106920, retrovirus particles displaying a functional antibody fragment is disclosed. These inventors fused the gene coding for a functional antibody fragment (250 amino acids) at the 5'-end of the gene coding for the complete Moloney Murine Leukemia Virus envelope protein (Pr80env) and following transfection in an ecotropic packag
REFERENCES:
Valesia Wittmann et al. J Virol. vol. 68, No. 7, Jul. 1994, p 4609-4619.
Jones et al. Nature. vol. 373. Feb. 9, 1995, p 539-544.
Bui Phuong T.
Oxford Biomedica (UK) Limited
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