Molecules containing at least one peptide sequence carrying one

Details Molecules containing at least one peptide sequence carrying one Molecules containing at least one peptide sequence carrying one

1988-10-06

1997-02-04

Cunningham, Thomas M.

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Amino acid sequence disclosed in whole or in part; or...

4241921, 4241931, 4242681, 4242721, 530326, 530350, 530395, 530403, A61K 39015, C07K 14445

Patent

active

055995420

DESCRIPTION:

BRIEF SUMMARY
The parasites responsible for malaria in man, especially Plasmodium falciparum and Plasmodium vivax to mention only the principal ones among them, exhibit various morphologies in the human host and express different antigens depending on their localization in the organism of the infected host. The morphological and antigenic differences of these parasites in the course of their life cycles in man make it possible to define at least four distinct stages of development.
The very first stage of development of the parasite in man corresponds to the sporozoite form introduced into the blood of the host by bites of insect carriers of the parasite. The second stage corresponds to the passage of the parasite into the liver and to the infection of the hepatic cells in which the parasites develop to form the hepatic schizonts which release the hepatic merozoites as a result of bursting. The third stage is characterized by the infection of the blood erythrocytes by the asexual forms (merozoites) of the parasite; this erythrocytic stage of development of the parasite corresponds to the pathogenic phase of the disease. The fourth stage corresponds to the formation of sexual forms (or gametocytes) which will become the extra-cellular gametes in the mosquito.
It is known that numerous studies have been undertaken to isolate from strains of parasites which are infectious for a human host polypeptide fractions in order to provide an in vitro diagnosis of malaria by detection of the corresponding antibodies, on the one hand, and in order to attempt to vaccinate against malaria, on the other.
For example, banks of cloned cDNAs derived from the sporozoites of Plasmodium falciparum have been established by ENEA et al. (1984) Science, vol. 225, 628-630. It was recognized that these banks comprised clones likely to express immunogenic polypeptides containing repetitive units of 4 amino acids specific for the circumsporozoite antigen (of P. falciparum).
However, little work has been carried out on the hepatic forms of the parasites responsible for malaria. The morphology of the hepatic forms was described for the first time in 1948 on the basis of biopsies on infected human volunteers (Trans. Roy. Soc. Trop. Med. Hyg., 41, 785 (1984)). It was possible to describe a specific antigen of the hepatic stage of P. falciparum in the liver of South American monkeys insensitive to the blood forms of the parasite but in which the hepatic forms can develop (Am. J. Trop. Med. Hyg., 33, (3) 336-341 (1984)).
The detection of the localization of the specific antigen(s) of the liver (hereafter designated by ISA for "Liver Specific Antigen") was carried out by means of immunofluorescence throughout the stages of maturation of the schizont. It is localized at the periphery of the parasite 5 to 40 microns in size; subsequently, it is distributed between the cytomeres or bundles of merozoites when the schizonts attain between 50 and 100 microns. It is distinct from the surface antigens of the sporozoites and the antigen shared by the schizonts of the blood and the liver which give an immunofluorescent image in the interior of the parasite.
Although it is henceforth possible to cultivate the hepatic forms of P. falciparum in human hepatocytes (Science, 227, 440 (1985)), the low yield of mature forms of the parasite by the in vitro and in vivo methods of culture does not permit biochemical analysis of the antigen produced at the hepatic stage.
It has also been observed that individuals suffering from malaria possess a very high level of antibodies directed against the LSA. The LSA seems to be a very powerful immunogen, among the most powerful of all the antigens synthesized at the various stages of development of the parasite. On the other hand, the level of antibodies directed against the forms of the blood stages of the parasite is sometimes very low, and consequently the diagnosis carried out on the basis of antigens specific for the blood stages can sometimes be falsely negative.
One of the aims of the present invention is precisely that of making

REFERENCES:
Druilh, P. et al., Am. J. Trop. Med. Hyg. 33(3):336-341, "Species-and stage-specific antigens in exoerytrhocytic stages of Plasmodium falciparum". Date 1984.
Fidock, D. A. et al., J. Immunology 153:190-204, "Plasmodium falciparum liver stage antigen-1 is well conserved and contains potent B and T cell determinants". Date 1994.
Guerin-Marchand, C. et al., Nature 329:164-167, "A liver-stage specific antigen of Plasmodium falciparum characterized by gene cloning". Date. Sep. 10, 1987.
Shortt, H. E. et al., Transactions of the Royal Society of Tropical Medicine and Hygiene 41(6):785-795, "The pre-erythrocytic development of Plasmodium cynomolgi and Plasmodium vivax". Date. May 1948.
Zhu, J. et al. Mol. Biochem. Parasitol. 48:223-226, "Structure of Plasmodium falciparium liver state antigen-1". Date 1991.

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