Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...
Patent
1998-01-05
2000-02-01
Housel, James C.
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
4242361, 4242411, 4242611, 4241841, 530350, A61K 3900, A61K 3902, A61K 39108, A61K 39106
Patent
active
060199733
DESCRIPTION:
BRIEF SUMMARY
This application is filed as a .sctn. 371 application of PCT/SE96/00570, filed May 2, 1996 with a priority claim to national application 9501682-0, filed May 5, 1995 in Sweden.
The present invention relates to hybrid molecules between heat-labile enterotoxin B subunit (LTB) and cholera toxin B subunit (CTB). Immunogenic proteins comprising such hybrid molecules, optionally fused to immunoreactive amino-acid sequences of or from cells or viruses, may be used as immunogenic components in vaccines, e.g. in a broad spectrum vaccine against enterotoxin-induced diarrhoea.
BACKGROUND
Cholera remains an important cause of illness in many developing countries and has been estimated to result in more than 200,000 deaths each year. Infection with enterotoxigenic E. coli (ETEC) is the most frequent cause of diarrhoea in the developing world and amongst travellers; it is responsible for more than one billion diarrhoeal episodes and one million deaths annually. Infection with ETEC is also an important cause of disease in animals For both cholera and ETEC infections there is a great need for effective vaccines.
In both cholera and ETEC infections, the primary cause of diarrhoea is the action of an enterotoxin released by the infecting organisms in the intestine; in the case of cholera cholera toxin (CT) and in the case of ETEC heat-labile enterotoxin (LT). The two toxins are closely related both structurally and functionally, each consisting of a toxic A subunit (CTA or LTA respectively) surrounded by five identical B subunits (CTB or LTB respectively) (Spangler, 1992). The B subunit pentamers are responsible for the binding of the toxin to GM1 ganglioside receptors present on the surface of intestinal epithelial cells (Holmgren, 1981); LT can also bind to structurally related galactoprotein receptors (Holmgren and Fredman, et al., 1982).
Although both proteins may exhibit internal variation in a few amino-acid residues, e.g. in human versus animal ETEC isolates and in classical versus El Tor biotype cholera strains, LTB and CTB show a high degree of homology with 85% conservation of amino acids in the mature protein (FIG. 1) and there is evidence from crystallographic studies that LTB and CTB pentamers are also structurally similar (Sixma and Pronk, et al., 1991, Sixma and Kalk, et al., 1993, Merritt and Sarfaty, et al., 1994). There is also a high degree of immunological cross-reactivity between the two molecules (Svennerholm and Wickstrom, et al., 1986) despite the fact that the majority of antibodies are directed against structural features of assembled pentamers; a further indication of the structural similarity between the two molecules.
CT has been found to be an effective oral immunogen that gives rise to intestinal IgA responses directed mainly against the B subunit. Furthermore, oral administration of CTB alone has also been found to effectively stimulate similar responses and especially in humans, CTB has been found to be a strong immunogen in the absence of either the adjuvant or toxic effects of the holotoxin. These responses are associated with high-level although relatively short-term (ca. 6-9 months) protection against challenge or natural infection with Vibrio cholerae and a much longer-lasting immunological memory (Svennerholm and Sack, et al., 1982, Svennerholm and Gothefors, et al., 1984, Svennerholm and Jertborn, et al., 1984, Clemens and Sack, et al., 1990, Quiding and Nordstrom, et al., 1991).
Antitoxin antibodies appear to act synergistically in their protective action together with intestinal IgA antibodies directed against bacterial cell-associated antigens such as the lipopolysaccharide (LPS) of V. cholerae O1 (Svennerholm and Holmgren, 1976) or of the novel serotype O139 (J. Holmgren, et al., unpublished). Based on these findings an oral vaccine against cholera has been developed consisting of CTB together with killed whole cells of V. cholerae O1 (Holmgren and Svennerholm, et al., 1992) which has given rise to protection lasting several years (Clemens and Sack, et al., 1990) and which is p
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Holmgren Jan
Lebens Michael R.
Devi S.
Housel James C.
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