Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Recombinant virus encoding one or more heterologous proteins...
Patent
1995-06-28
2000-05-09
Scheiner, Laurie
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Recombinant virus encoding one or more heterologous proteins...
435 691, A61K 3912
Patent
active
060600640
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to biologically useful particles. In particular it relates to modified particles derived from the yeast retrotransposon Ty. Particles formed from such proteins are immunogenic and can be used in immunotherapeutic or prophylactic vaccines or as diagnostic agents.
An ideal immunogen is a polymer of multiple antigen determinants assembled into a high molecular weight, particulate complex. A substantial disadvantage of most antigens produced by recombinant DNA techniques for vaccines is that they are usually produced as simple monomeric proteins. This is not the ideal configuration of an immunising antigen as it does not readily permit the cross-linking of the components of the immune system. Such crosslinking is required for maximum stimulations of humoral and cellular immunity. For these reasons it would be advantageous to develop polyvalent, particulate carrier systems for immunising antigens.
WO-A-8803562 and WO-A-8803563 describe the use of certain fusion proteins derived from retrotransposons or RNA retroviruses for pharmaceutical, diagnostic or purification applications. Such particles are designated virus-like particles (VLPs) when derived from the yeast retrotransposon Ty. The above published PCT applications note that polyvalent particles are useful for immunisation purposes because their polyvalent nature provides that more antibodies will be raised against the particulate antigens used. The particles are formed of fusion proteins having a particle-forming sequence and, in some embodiments at least, an antigenic sequence. In the examples, the antigenic sequence is positioned C-terminal to the particle-forming sequence.
While the above approach is promising, a potential difficulty is that insertion of the antigen at the C-terminal end of the particle-forming protein may not in all cases be optimal for presentation to the immune system. Animals immunised with recombinant VLPs may elicit a higher titre response to the Ty component than to the added antigen. It would therefore be highly advantageous to construct antigen-presenting particles where the antibody response to the added antigen is augmented. Such particles might also have enhanced ability to stimulate a cell-mediated immune response, such as a T-cell response, a Cytotoxic T-lymphocyte (CTL) reponse or a Natural Killer (NK) cell response. It would further be advantageous if, following immunisation with such particles, the antibody response to the particle-forming moiety was reduced or preferably prevented.
One way to improve the presentation of the antigenic sequence to the immune system might be to insert the antigenic sequence of interest within the particle-forming sequence. However, correct insertion of the antigenic site within the particle-forming protein is likely to be critical for particle formation. Insertions might disrupt the secondary and tertiary structure determinants of the monomer, or the quaternary interactions between monomers necessary for particle formation.
One approach to deduce suitable surface-exposed insertion sequences has been to use the understanding of the three-dimensional structure of viruses elucidated by X-ray crystallography. Such precise analysis of the structure of the polio virus has enabled particulate chimaeric proteins to be created whereby heterologous antigenic sequences are substituted for amino-acids present in the suface-exposed epitopes of this virus (Dedieu et al., J. Virol. (1992) 66 3161-3167; Burke et al, Nature (1988) 332 81-82; Evans et al., Nature (1989) 339 385-388). However, these polio virus constructions are limited by the need to produce a viable virus; even some very short sequences cannot be tolerated.
Detailed analysis as described for poliovirus is not possible for proteins which have not yet been crystallised. Where particles have a well-characterised tertiary .beta.-barrel structure, internal insertions of heterologous antigenic sequences into presumed surface exposed regions have been made using predictive models based on sequence alignment. For exa
REFERENCES:
Adams et al., 1987 Nature 329:68-70.
Griffiths et al., 1991 J. Virol. 65:450-456.
Harris et al., 1992 Immunol. 77:315-321.
Reeck et al., 1987 Cell 50:667.
Lewin, 1987 Science 237:1570.
Adams Sally Elizabeth
Burns Nigel Robert
Richardson Simon Mark
British Biotech Pharmaceuticals Limited
Parkin Jeffrey S.
Scheiner Laurie
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