Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Derived from – or present in – food product
Reexamination Certificate
2002-06-24
2004-09-21
Smith, Lynette R. F. (Department: 1645)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Derived from, or present in, food product
C424S093400, C424S093450, C424S164100, C426S071000, C426S061000, C426S583000, C426S093000, C514S002600, C514S007600, C514S008100, C514S055000, C514S056000, C514S024000
Reexamination Certificate
active
06793921
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to specific antibodies for use in preparing pharmaceutical compositions useful for the prevention or treatment of gastritis, gastric ulcers and duodenal ulcers caused by infection of
Helicobacter pylori
(hereinafter referred to as
H. pylori
or Hp), and for use as an additive to foods useful for the prevention of gastritis, gastric ulcers and duodenal ulcers.
At present it is believed that eradication of
H. pylori
in the stomach is essential for treating peptic ulcers fully. The combination of antibiotics and suppressors of gastric acid secretion has been generally proposed as a therapy for effective eradication of
H. pylori
as described below.
H. pylori
is a gram-negative spiral rod-shaped bacterium having some flagella at one end and inhabiting the human gastric mucosa. Marshall, B. J. and Warren, J. R. in Australia reported in 1983 that this bacterium was frequently detected in stomach biopsy specimens from patients with gastric ulcers. At that time this bacterium was named
Campylobacter pylori
since it resembles Campylobacter in morphology and growth characteristics. Later, it was found that the bacterium is different from Campylobacter in the fatty acid composition of its outer membrane and sequence of ribosome 16S-RNA. Therefore, the bacterium is now referred to as
Helicobacter pylori
and belongs to a newly established genus of Helicobacter.
Since then, many reports have been published based on epidemiological studies, indicating that this bacterium causes gastritis, gastric ulcers and duodenal ulcers and is associated with diseases such as gastric cancer. Once
H. pylori
colonizes gastric mucosa, it cannot be eradicated in the stomach and continues to inhabit the stomach, although the immune response to infection thereof is strong, i.e., the antibody titer is high. Therefore, unless
H. pylori
is completely eliminated from the stomach by antibiotic therapy, the condition of infection will return to the same level as before treatment within about a month after the administration of antibiotics is stopped. Additionally, the pH of the stomach is maintained very low by HCl, which is a strong acid, and therefore most antibiotics are apt to be inactivated. For this reason, the combination of an antibiotic and a proton pump inhibitor which strongly suppresses the secretion of gastric acid is utilized often in a greater dose than usual for eradication of
H. pylori
. Recently, a new treatment employing a combination of bismuth subsalicylate, metronidazole, and tetracycline has proved to have the highest rate of elimination of
H. pyroli
, but metronidazole in this combination is known to cause the rapid emergence of an antibiotic-resistant strain when used alone. In developing countries this medicine has been used widely for treating diarrhea patients, and as a result there is a high rated infection with metronidazole-resistant
H. pylori
. Thus, the administration of antibiotics for a long time has the serious problems of increasing antibiotic-resistant strains as well as causing side effects.
At present, an immunological therapy approach using an oral vaccine has been proposed in order to solve problems such as side effects and increase of antibiotic-resistant strains by treatment with antibiotics for the eradication of the bacteria. However, for this purpose it is essential to develop model animals for Hp infection. It has been reported that Hp infection tests have been conducted using rats, mice, rabbits, dogs, pigs, and monkeys, and tests using dogs, pigs and monkeys have been successful. However, Hp cannot easily infect small animals such as mice and rats, and infection tests require complicated conditions. For example, germ-free animals are required for infection or fresh isolates are required for maintaining infection for a long time. These requirements have obstructed studies aimed at developing new methods for prevention and treatment.
For example, it was reported by Marchetti, M. et al. in Science, vol. 267, pp1655-1658 (1995) that 80% of Hp infection was inhibited by oral immunization using a mouse model for evaluating the efficacy of Hp oral vaccine. However, this oral vaccine preparation had heat-labile toxin (LT) derived from
E. coli
as an adjuvant. Generally. in such experiments using an oral vaccine, the vaccine preparation has cholera toxin in addition to LT derived from
E. coli
, and mucosal immunity cannot be attained without these adjuvants. LT from
E. coli
and cholera toxin have a high level of toxicity, and this vaccine method has many unsolved problems in respect to safety in its practical application to humans. Also, the vaccine is predominantly used for prevention, and therefore it has no effect on patients who have already been infected with Hp.
As a new attempt to inhibit Hp, Aiba et al. (The Meeting of the 30th Japan Germ-free Animal Gnotobiology Society, Program and Abstracts, pp22, Requested Title 18, New Attempt for Inhibiting
Helicobacter pylori
, January 1997) used germ-free mice as a model of Hp infection and studied (i) the effect of
Lactobacillus salivarius
as probiotics on inhibition of Hp and (ii) the effect of oral administration of anti-Hp antibodies obtained from the yolk of the eggs of hens immunized with formalin-killed whole cell of Hp on inhibition of Hp. In case (i), the number of Hp in the stomach of the Hp infected mice in an administered group became 10-1000 times less than that of a control group. In case (ii), the number of Hp in the stomach of an administered group became 10 times less than that of a control group.
However, these results were obtained using mice which do not have normal flora in the oral cavity, stomach and intestines, and it is not expected that such results can be obtained in conventional mice having normal flora. Generally, when mice having inherent normal flora are inoculated with human lactic acid bacteria, the bacteria are eliminated by the normal flora and do not colonize. Also, the antibodies used in the above experiments were those against whole cells of Hp, and the number of Hp in the stomach became only 10 times less than that of the control group, i.e., Hp was not eliminated completely. Furthermore, there is no reference to the relation between the decrease of Hp and the lessening of gastritis.
Japanese Patent Application Kokai No. 4-275232 also discloses the use of specific antibodies, but it merely discloses antibodies obtained from the eggs of hens immunized against Hp whole cells as an antigen. It describes a food for use in prevention of gastritis, gastric ulcer or duodenal ulcer, comprising as an active ingredient antibodies obtained from the eggs of hens immunized with Hp whole cell as an antigen, the antibodies being specific for the antigen, but the effect of the specific antibodies is not clear. The efficacy of the obtained antibodies against whole cells is evaluated by utilizing the fact that Hp adheres to mucin in pig gastric mucosa in vitro, and the results are that egg antibodies against Hp whole cells inhibit the adhesion of Hp to gastric mucosa. However, the in vitro tests were conducted in a mild environment of pH 7.4, and therefore it is questionable whether the obtained data accurately indicate the results to be obtained in a strongly acidic environment of pH 1-3 in the stomach. The confirmation of the effect of eliminating Hp in a strongly acidic stomach requires animals as an Hp infection model in experiments. The above-described patent application does not refer to such experiments, and therefore it is not clear whether the administration of egg antibodies against Hp whole cells can promote the elimination of Hp. Also, there is no reference as to whether the antibodies can suppress the occurrence of gastritis.
It is disclosed in transactions of Japan Agricultural Chemistry Society, 71, pp52, 20p22 (1997) that the egg antibodies against Hp whole cells have an inhibitory effect on Hp growth. However, the antibodies may have the same problems as explained above since the antigen used in immunizing h
Ariga Masato
Icatlo, Jr. Faustino C.
Kimura Nobutake
Kodama Yoshikatsu
Nisshin Pharma Inc.
Portner Ginny Allen
Smith Lynette R. F.
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