Recombinant DNA molecules encoding aminopeptidase enzymes and th

Details Recombinant DNA molecules encoding aminopeptidase enzymes and th Recombinant DNA molecules encoding aminopeptidase enzymes and th

1995-01-09

2000-05-23

Caputa, Anthony C.

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Preparing compound containing saccharide radical

435 691, 435325, 435 697, 435212, 435362, 4352523, 4353201, 435365, 435367, 43525233, 43525411, 435183, 536 231, 536 232, 536 234, 536 235, 4241841, 424 941, 4242651, 4241991, 530300, 530350, 5303886, 930240, C12N 1530, C12N 1552, C12N 1557, A61K 3900

Patent

active

060665033

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to the preparation of protective antigens by recombinant DNA technology for use as anthelmintic agents and as protective immunogens in the control of diseases caused by helminth parasites.
Helminth parasites are responsible for a wide range of diseases and infestations of domestic animals which, leading as they do to loss of production and even animal mortality, are of considerable economic importance. Thus for example, the blood feeding nematode Haemonchus infects the lining of the gastrointestinal tract of ruminants, causing anaemia and weight loss and if untreated frequently leads to death. Animals infected with the related non-blood feeding nematode Ostertagia similarly fail to thrive and may die if untreated. Other genera of helminths of economic importance include Trichostrongylus and Nematodirus which cause enteritis in various animal, and trematodes.
Problems are also caused by nematodes such as hookworms (eg. Hecator, Ancylostoma, Uncinaria and Bunostomum spp) and flukes (eg. Fasciola, Paramphistomum and Dicrocoelium) and their relatives which in addition to ruminants and domestic pets, also infect humans, frequently with fatal results.
Control of helminth parasites presently relies primarily on the use of anthelmintic drugs combined with pasture management. Such techniques have a number of drawbacks however--frequent administration of drugs and pasture management are often not practical, and drug-resistant helminth strains are becoming increasingly widespread.
There is a therefore a need in this field for an effective anti-helminth vaccine and many efforts have been concentrated in this area in recent years. However, as yet there are no commercially available molecular or sub-unit vaccines for the major helminth species, particularly for the gastrointestinal nematodes of ruminants, such as Haemonchus and Ostertagia.
Most promising results to date have been obtained with novel proteins isolated from Haemonchus, which have potential as protective antigens not only against Haemonchus but also against a range of other helminths. In particular the protein doublet H110D, found at the luminal surface of the intestine of H. contortus has been shown to confer protective immunity against haemonchosis in sheep.
H110D from H. contortus has an approximate molecular weight of 110 kilodaltons (kd) under reducing and non-reducing conditions, as defined by SDS-PAGE, and is describe din WO 88/00835 and WO 90/11086. The term "H110D" as used herein refers to the protein doublet H110D as defined in WO 88/00835 and WO 90/11086. Corresponding proteins have also recently been shown in other helminth species, eg. Necator americanus.
A number of methods for the purification of H110D have ben described in WO 88/00835 which suffice for the characterisation of the protein, and may be scaled up to permit production of the protein in experimentally and commercially useful quantities. There is however a need for an improved and convenient source from which to prepare not only H110D but also related antigenic proteins, especially for a process based on recombinant DNA technology and expression of the proteins in suitably transformed prokaryotic or eukaryotic organisms.
The present invention seeks to provide such an improved procedure. Sequence determination of cDNAs for H110D from Haemonchus contortus has been performed and the predicted amino acid sequences have been found to display homology with a family of integral membrane aminopeptidases (systematic name: .alpha.-amino acyl peptide hydrolase (microsomal)).
The mammalian integral membrane aminopeptidases are located in several tissues, eg. on the microvillar brush border of intestines, and kidney. Their role in the kidney is unclear, but in the intestine their function is to cleave the small peptides which are the final products of digestion (for reviews, see Kenny & Maroux, 1982; Kenny & Turner, 1987; Noren et al, 1986; Semenza, 1986).
In one aspect the present invention thus provides nucleic acid molecules comprising one or more nucleotide se

REFERENCES:
patent: 4879213 (1989-11-01), Fox et al.
Lehniger "Biochemistry" 2nd ed. Worth Publishers, p. 63.
Burgress et al. J. Cell Biol. (1990) vol. 111, 2129-2138.
Lazar et al. (1988) Mol. and Cell. Biol. vol. 8(3), 1247-1252.
Olsen et al., (1988) FEBS Lett. vol. 238(2), 307-314.
Look et al. (1989) J. Clin. Invest. vol. 83(4), 1299-1307.
Watt et al., "Amino Acid Sequence Deduced from a Rat Kidney cDNA Suggests It Encodes the Zn-peptidase Aminopeptidase N*", Journal of Biol. Chem., vol. 264, No. 10, pp. 5480-5487, Apr. 5, 1989.
Wu et al., "Molecular cloning of the murine BP-1/6C3 antigen: A member of the zinc-dependent metallopeptidase family", Proc. Natl., Acad. Sci. USA, vol. 87, pp. 993-997, Feb. 1990 (Immunology).

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