Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1997-12-23
2004-07-13
Smith, Lynette R. F. (Department: 1645)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S023100, C514S04400A, C435S006120, C435S069100, C435S173300, C435S173300, C435S252330, C435S320100
Reexamination Certificate
active
06762295
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to protective Helicobacter antigens, especially
H. pylori
antigens, and in particular to the use of these antigens for the treatment of, or prevention of, gastroduodenal disease associated with
H. pylori
infection.
BACKGROUND OF THE INVENTION
Helicobacter pylori
is a gram negative, spiral bacterium which infects the lining of the human stomach. It is widely distributed, chronically infecting perhaps half the world's population. The bacterium spreads from person to person by oral-oral or faecal-oral transmission, there being no recognised environmental reservoir.
Infection with the bacterium causes an inflammation of the gastric mucosa, or stomach lining. Usually this does not resolve, and infection and inflammation are believed to persist for many decades. Often this is not associated with symptoms, however this chronic infection is associated with an increased risk of a number of sequelae. A significant portion of those infected develop peptic ulceration of the duodenum or stomach, when the infection process disrupts the usual protective mechanisms the stomach has against its own digestive products. Also, long periods of infection increase the risk of the development of adenocarcinomas or lymphomas of the stomach wall.
Therefore, prevention or treatment of
H. pylori
infection has the potential to prevent considerable mortality and morbidity resulting from the sequelae of chronic infection.
In early experiments,
H. pylori
did not infect conventional laboratory animals. However, a laboratory mouse model of
H. pylori
infection, using the closely related organism,
Helicobacter felis
, has been developed (Lee et al., 1990; Dick-Hegedus and Lee, 1991). This model has proven very useful in screening new antimicrobial therapeutic regimes.
H. felis
is a spiral shaped bacterium that shares a very close DNA homology with
H. pylori
. The bacterium colonises the mouse stomach in a similar manner to the way that
H. pylori
colonises the human stomach. The main ecological niche is gastric mucus, and colonisation is mainly seen in the antrum of the stomach. In germfree mice,
H. felis
infection induces a gastritis that is very similar to the human
H. pylori
infection, with a chronic inflammation of mononuclear cells accompanied by a polymorphonuclear leucocyte infiltration. Infection with either organism results in the induction of a similar raised systemic humoral immune response against
H. pylori
and
H. felis
respectively (Lee et al., 1990).
The
H. felis
model has proved to be very predictive of the efficacy of anti-
H. pylori
therapy in humans. Thus, monotherapy with agents with high in vitro activity such as erythromycin show no significant in vivo effect against
H. felis
in mice, just as erythromycin has no ant-
H. pylori
effect in humans, despite its high antimicrobial effects in vitro. In contrast, the triple therapy regimens of a bismuth compound, metronidazole, and tetracycline or amoxycillin lead to a very high eradication rate in
H. felis
infected mice (Dick-Hegedus and Lee, 1991). Such therapies are among the most successful human anti-
H. pylori
regimens.
The
H. felis
model has also been used to demonstrate that mice can be orally immunised with Helicobacter antigens, either to protect them from becoming infected (Chen et al, 1992), or to treat them when they are already infected so as to eradicate the infection (Doidge et al, 1994). Antigens that have been used in these vaccines include disrupted cellular preparations from either
H. felis
or
H. pylori
, and the bacterial enzyme urease from
H. felis
or
H. pylori
or subunits thereof, produced from
E. coli
clones expressing all or part of the
H. pylori
urease molecule (Michetti et al, 1994; see also International Patent Publications Nos. WO 90/04030, WO 93/07273 and WO 94/09823).
H. pylori
heat shock protein (Hsp or HSP) has also been shown to be a protective antigen (Ferrero et al., 1995).
International Patent Publication No. WO 93/18150 (Application No. PCT/EP93/00472) discloses vaccines or therapeutic compositions comprising one or more of recombinant
H. pylori
cytotoxin (CT or VacA),
H. pylori
cytotoxin-associated immunodominant antigen (CAI or CagA) or
H. pylori
heat shock protein, optionally together with
H. pylori
urease. International Patent Publication No. WO 95/27506 (Application No. PCT/FR95/00383) discloses an anti-
H. pylori
immunising composition containing a substantially purified
H. pylori
catalase as the active ingredient; and International Patent Publication No. WO 95/14093 (Application No. PCT/EP93/03259) discloses an immunogenic composition capable of inducing protective antibodies against Helicobacter infection which comprises at least one urease structural polypeptide from
H. pylori
or
H. felis
and optionally a urease-associated heat shock protein or chaperonin from Helicobacter.
The fact that antigens derived from
H. pylori
can be used to protect mice from
H. felis
infection suggests that there are cross-reactive, and cross-protective antigens between the two species. That is, that there are molecules present in
H. pylori
, which can induce immune responses in mice that recognise targets on
H. felis
, thus protecting the mice from
H. felis
infection. If an immune response to these
H. pylori
molecules will protect mice from
H. felis
infection, it is likely that similar immune responses will protect humans from
H. pylori
infection, or if already infected, cure them of it. Urease has been demonstrated to be such a cross-protective molecule in the
H. felis
mouse model (Michetti et al, 1994).
In work leading to the present invention, in order to identify further cross-reactive and cross protective antigens, a DNA library from an
H. pylori
strain has been constructed and screened with serum from mice that had been orally immunised with a vaccine prepared from disrupted
H. felis
cells and a mucosal adjuvant, with the aim of identifying
E. coli
clones expressing
H. pylori
proteins recognised by anti-
H. felis
antibodies and of subsequently identifying the antigenic protective
H. pylori
proteins.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides an antigenic preparation for use in the treatment or prevention of Helicobacter infection in a mammalian host, which comprises an at least partially purified preparation of at least one Helicobacter antigen selected from the group consisting of:
(i) an antigen having a molecular mass of approximately 19 kDa which is processed into a mature form having a molecular mass of approximately 17 kDa;
(ii) an antigen having a molecular mass of approximately 13 kDa;
(iii) an antigen having a molecular mass of approximately 36 kDa;
(iv) an antigen having a molecular mass of approximately 50 kDa;
(v) an antigen having a molecular mass of approximately 29 kDa; and
(vi) immunogenic fragments of any of antigens (i) to (v) above which are capable of eliciting a specific protective immune response in a mammalian host.
In another aspect, the present invention provides an isolated Helicobacter antigen for use in the treatment or prevention of Helicobacter infection in a mammalian host, selected from the group consisting of:
(i) an antigen having a molecular mass of approximately 19 kDa which is processed into a mature form having a molecular mass of approximately 17 kDa;
(ii) an antigen having a molecular mass of approximately 13 kDa;
(iii) an antigen having a molecular mass of approximately 36 kDa;
(iv) an antigen having a molecular mass of approximately 50 kDa; and
(v) an antigen having a molecular mass of approximately 29 kDa; and
(vi) immunogenic fragments of any of antigens (i) to (v) above which are capable of eliciting a specific protective immune response in a mammalian host.
Each of the above antigens is further characterised by being reactive with anti-
H. felis
antibodies.
Preferably, antigen (i) above comprises an amino acid sequence substantially corresponding to the deduced sequence of clone B4.6 hereinafter (SEQ ID NO.10
Doidge Christopher Vincent
Hocking Dianna Margaret
Lee Adrian
Radcliff Fiona Jane
Webb Elizabeth Ann
CSL Limited
Foley & Lardner
Portner Ginny Allen
Smith Lynette R. F.
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