Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...
Patent
1996-04-29
2000-12-26
Caputa, Anthony C.
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
4242691, A61K 39002
Patent
active
061654698
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The invention concerns the use of epitope-bearing regions of the 170 kD subunit of Entamoeba histolytica Gal/GalNAc adherence lectin which are produced recombinantly in procaryotic systems in diagnosis and as vaccines. Thus, the invention relates to the determination of the presence, absence or amount of antibodies raised by a subject in response to infection by E. histolytica using these peptides and to vaccines incorporating them. This invention also particularly relates to reagents specific for a novel variant of the 170 kD subunit of E. histolytica Gal/GalNAc adherence lectin and to the gene (hgl3) which encodes this novel subunit form, which represents the third member of the multigene family encoding this 170 kD subunit.
BACKGROUND ART
Entamoeba histolytica infection is extremely common and affects an estimated 480 million individuals annually. However, only about 10% of these persons develop symptoms such as colitis or liver abscess. The low incidence of symptom occurrence is putatively due to the existence of both pathogenic and nonpathogenic forms of the amoeba. As of 1988, it had been established that the subjects who eventually exhibit symptoms harbor pathogenic "zymodemes" which have been classified as such on the basis of their distinctive hexokinase and phosphoglucomutase isoenzymes. The pathogenic forms are not conveniently distinguishable from the nonpathogenic counterparts using morphogenic criteria, but there is an almost perfect correlation between infection with a pathogenic zymodeme and development of symptoms and between infection with a nonpathogenic zymodeme and failure to develop these symptoms.
It is known that E. histolytica infection is mediated at least in part by the "Gal/GalNAc" adherence lectin which was isolated from a pathogenic strain and purified 500 fold by Petri, W. A., et al., J Biol Chem (1989) 264:3007-3012. The purified "Gal/GalNAc" lectin was shown to have a nonreduced molecular weight of 260 kD on SDS-PAGE; after reduction with beta-mercaptoethanol, the lectin separated into two subunits of 170 and 35 kD MW. Further studies showed that antibodies directed to the 170 kD subunit were capable of blocking surface adhesion to test cells (Petri, et al. J Biol Chem (1989) supra). Therefore, the 170 kD subunit is believed to be of primary importance in meditating adhesion.
In addition, the 170 kD subunit is described as constituting an effective vaccine to prevent E. histolytica infection in U.S. Pat. No. 5,004,608 issued Apr. 2, 1991.
Studies of serological cross-reactivity among patients having symptomology characteristic of E. histolytica pathogenic infection, including liver abscess and colitis, showed that the adherence lectin was recognized by all sera tested (Petri, Jr., W. A., et al., Am J Med Sci (1989) 296:163-165). The lectin heavy subunit is almost universally recognized by immune sera and T-cells from patients with invasive amebiasis (Petri, et al., Infect Immun (1987) 55:2327-2331; Schain, et al., Infect Immun (1992) 60:2143-2146).
DNA encoding both the heavy (170 kD) and light (35 kD) subunits have been cloned. The heavy and light subunits are encoded by distinct mRNAs (Mann, B., et al., Proc Natl Acad Sci USA (1991) 88:3248-3252) and these subunits have different amino acid compositions and amino terminal sequences. The sequence of the cDNA encoding the 170 kD subunit suggests it to be an integral membrane protein with a large cysteine-rich extracellular domain and a short cytoplasmic tail (Mann, B., et al., Proc Natl Acad Sci USA (1991) supra; Tannich, et al., Proc Natl Acad Sci USA (1991) 88:1849-1853). The derived amino acid sequence of the 170 kD lectin shows that the extracellular domain can be divided into three regions on the basis of amino acid composition. The amino terminal amino acids 1-187 are relatively rich in cysteine (3.2%) and tryptophan (2.1%). Amino acid sequence at positions 188-378 does not contain cysteine, and the amino acid sequence at positions 379-1209 contains 10.8% cysteine residues. The obtention of
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Mann Barbara J.
Petri William A.
Caputa Anthony C.
Gucker Stephen
Livnat Shmuel
University of Virginia
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