Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Parasitic organism or component thereof or substance...
Patent
1994-10-04
1998-02-24
Cunningham, Thomas M.
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Parasitic organism or component thereof or substance...
4241851, 4242681, 435 693, 4353201, 530300, 530350, 530395, 536 235, A61K 39015, C07K 14445
Patent
active
057209596
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB93/00367, filed Feb. 22, 1993.
FIELD OF THE INVENTION
The present invention relates to the identification of antigenic portions of malaria proteins, their expression in host cells, particularly bacteria, and their potential use as a vaccine.
BACKGROUND OF THE INVENTION
Malaria is caused by protozoal parasites of the genus Plasmodium. There are four species that infect man, P. falciparum P, vivax, P. malariae and P. ovale. Of these P. falciparum is largely responsible for acute and often fatal malaria, but there is significant morbidity associated with each malaria infection and a large proportion of the world's population is at risk from the disease. It has been estimated that malaria is a public health problem in areas where 40% of the world's population live and the disease has severe social and economic consequences for these communities. There has been a recent resurgence of the disease due to the abandonment or breakdown of control measures and to an increasing resistance of the vector to insecticides and falciparum malaria to chemotherapy. Thus there is an urgent need to develop a vaccine effective against malaria.
Most attempts to develop a vaccine have focused on trying to identify single proteins that are capable of inducing protective immune responses in the host against the relevant species and stage of parasite. This is in itself an enormous task because of the complexity of the parasite's life cycle, the number and diversity of antigens within the spectrum of polypeptides synthesised, and the superficial understanding we have of the important aspects of the immune system that control malaria. Nevertheless, several proteins have been identified by using monoclonal antibodies, sera from immune individuals and antibodies to fragments of genes expressed from libraries in bacteria. Using a variety of criteria, including the effects of antibodies in vitro or in vivo on the parasite's growth and development, direct immunization studies, and subcellular location or possible function of the protein, several vaccine candidates have been proposed.
One such candidate is the Merozoite Surface Protein-1 (abbreviated to MSP1, but also known as MSA1, PMMSA, P.190 or gP195) located on the exterior of the merozoite, the parasite stage which invades erythrocytes. MSP1 is found on the merozoite surface of all malaria parasite species and is therefore an ideal target for a candidate malaria vaccine. The precursor protein is, in fact, proteolytically processed to form a complex of Parasitology 94, 199-208).
It has been shown that the protein purified from P. falciparum will protect Sci. 84, 3014-3018). Two different reports have shown that monoclonal antibodies to this molecule will inhibit invasion in vitro (Pirson & study the target of the antibodies was identified as a 19 kDa fragment derived from the C-terminus of the precursor and which is retained on the merozoite surface during invasion of erythrocytes. A monoclonal antibody specific for the homologous protein expressed by P. yoelii inhibits growth of this parasite in vivo after passive transfer to infected mice (Majarian been mapped to the C-terminal sequence of this protein (Burns et al.,
Antibodies to the C-terminal region of the precursor do not bind to the protein after it has been treated with reducing agents such as mercaptoethanol or dithiothreitol, suggesting that the numerous cysteine residues in this area are involved in specific disulphide bonding. Since it is a well known observation that proteins expressed as intracellular proteins in E. coli do not form correct disulphides, expression and secretion using the baculovirus/insect cell system has been used for the Parasitology 100, 177-183).
In the further development of these polypeptides towards a practical product, their isolation from the parasite is not a feasible proposition, therefore much current research is devoted to using recombinant DNA or peptide synthesis techniques to get round this problem. However, the expression of a gene sequence in bacte
REFERENCES:
patent: 4837016 (1989-06-01), Holder et al.
Blackman et al: "Proteolytic processing of the Plasmodium falciparum merozoite surface protein-1 produces a membrane-bound fragment containing two epidermal growth factor-like domains", Molecular and Biochemical Parasitology, 49 (1991) 29-34.
Holder et al: "Processing of the precursor to the major merozoite surface antigens of Plasmodium falciparum", Parasitology, vol. 94, No. 2, Apr. 1987, pp. 199-208.
Blackman, et al: "A single fragment of a malaria merozoite surface protein remains on the parasite during red cell invasion and is the target of invasion-inhibiting antibodies", J. Exp. Med., vol. 172, Jul. 1990, pp. 379-382.
Kaslow et al: "A vaccine candidate from the sexual stage of human malaria that containes EGF-like domains", Nature, vol. 333, May 1988, pp. 74-76.
Burns et al: "A protective monoclonal antibody recognizes an epitope in the carboxyl-terminal cysteine-rich domain in the precursor of the major merozoite surface antigen of the rodent malarial parasite, Plasmodium yoelii", Journal of Immunology, vol. 143, No. 8, Oct. 1989, pp. 2670-2676.
Smith, et al "Single step purification of polypeptides expressed in Escherichia coli as fusions with glutathione S-transferase", Gene, vol. 67, No. 1, Jul. 1988, pp. 31-40.
Chappel, et al: "Monoclonal antibodies specific for merozoite surface protein 1 in Plasmodium-falciparum recognize epidermal growth factor-like motifs", Abstract Gen Meet. Am Soc. Microbiol, vol. 92, No. 0, 1992, p. 61 .
Blackman Michael J.
Chappel Jonathan A.
Holder Anthony A.
Cunningham Thomas M.
Medical Research Council
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