Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Structurally-modified antibody – immunoglobulin – or fragment...
Reexamination Certificate
2000-10-31
2002-05-07
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Structurally-modified antibody, immunoglobulin, or fragment...
C424S141100, C424S157100, C530S388250, C530S388260
Reexamination Certificate
active
06383485
ABSTRACT:
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not applicable.
BACKGROUND OF THE INVENTION
The present invention relates to a method for modulating the activity of one or more enzymes that produce precursors of lipid metabolites associated with gastric inflammation, to reduce the deleterious effects of gastric inflammation and to enhance animal and human growth or improve feeding efficiency.
Enhancing animal growth or feed efficiency, can have substantial impact on, for example, the animal meat industry by reducing the high cost of feeding food-producing animals and directly improving profitability. For example, in the poultry industry, even a slight increase in broiler growth rate coupled with reduced feed consumption brings the broiler to market maturity faster at lower cost. With approximately seven billion broilers raised annually in the United States, significant savings are realized.
Methods are known for controlling feeding behavior by modulating the activity of gut peptides that control gastrointestinal motility. These gut peptides include cholecystokinin (CCK), the avian pancreatic polypeptide (aPP), bombesin, gastrin, somatostatin, and neuropeptide Y. Duke, G. E., “Recent Studies on Regulation of Gastric Motility in Turkeys,”
World's Poultry Science Association Invited Lecture,
pp. 1-8 (1991); Baile et al., “Hormones and feed intake,”
Proc. Nutr. Soc.,
42:113-27 (1983). The effect upon feeding behavior of physiological regulators other than the gut peptides is largely unknown.
One set of such regulators include inflammatory metabolites such as the leukotrienes and the prostaglandins which can have beneficial, as well as damaging, effects on the host.
In animals, linoleic acid is converted to arachidonic acid. Arachidonic acid is released (as arachidonate) from the sin2 position of membrane phospholipids by phospholipase A
2
(PLA
2
) and is converted by lipoxygenase or cyclooxygenase into precursors for biologically active prostaglandins and leukotrienes. Perhaps as a result of artificially high dietary linoleic acid levels, animals can contain high levels of the prostaglandin and leukotriene precursors.
Prostaglandins are C
20
fatty acids formed from arachidonic acid by cyclooxygenase activity. Prostaglandins cause inflammatory effects during gastrointestinal traumas, such as colitis and ulcers, and are involved in vasodilation, vasoconstriction, and stimulation of intestinal or bronchial smooth muscle. Prostaglandins are found in inflammatory exudates and can induce fever and erythema. Leukotrienes, which are formed from arachidonic acid in response to immunological or non-immunological leucocytes and macrophages stimulation, cause contraction of smooth muscle, such as intestinal smooth muscle, attract leukocytes and stimulate vascular permeability.
It may be possible to reduce inflammation by reducing gastrointestinal prostaglandin synthesis, perhaps by using selective inhibitors of cyclooxygenase-2, an enzyme expressed at inflammation sites. This would reduce or eliminate the need for standard nonsteroidal anti-inflammatory drugs which are known to have ulcerogenic side effects. However, Reuter et al. have shown that inhibition of cyclooxygenase products, such as prostaglandin, exacerbated colitis and increased inflammation-associated colonic injury. Reuter et al., “Exacerbation of Inflammation-associated Colonic Injury in Rat through Inhibition of Cyclooxygenase-2,
” J. Clin. Invest.,
98(9):2976-85 (1996). Likewise, Uribe et al. have shown that using indomethacin to inhibit prostaglandin synthesis causes intestinal ulcers. Uribe et al., “Endogenous Prostaglandins and Microflora Modulate DNA Synthesis and Neuroendocrine Peptides in the Rat Gastrointestinal Tract,”
Scand. J. Gastro.,
32:691-99 (1997). Other research has shown that prostaglandins are necessary for gut function repair. Blikslager et al., “Prostaglandins I
2
and E
2
Have a Synergistic Role in Rescuing Epithelial Barrier Function in Porcine Ileum,”
J. Clin. Invest.,
100(8): 1928-33 (1997).
These findings suggest that downregulating prostaglandin activity would be deleterious to an animal's gastrointestinal system.
BRIEF SUMMARY OF THE INVENTION
The present invention is summarized in that gastrointestinal inflammation is reduced, resulting in improved gut health, enhanced growth and increased feed efficiency in animals, without deleterious effect, by limiting bioavailability of a leukotriene and prostaglandin precursor.
In a related aspect, the invention is summarized in that the antibody can limit availability of arachidonic acid.
In another aspect of the invention, anti-PLA
2
antibodies are administered to an animal to increase growth or improve feed efficiency. The anti-PLA
2
antibodies limit availability of arachidonic acid, a precursor to inflammatory lipid metabolites such as leukotrienes and prostaglandins.
In yet another aspect of the invention, anti-PLA2 antibodies are administered to an animal to counteract inflammatory problems involving the gut, whether arising from exposure to endotoxin or infectious agents, or from inflammatory processes such as Crohn's.
It is an object of this invention to provide a method for reducing gastrointestinal tract inflammation, resulting in improved health, enhanced growth or increased feed efficiency in animals, without deleterious effect, by limiting availability of precursors to prostaglandin and leukotriene metabolites.
It is another object of the present invention to reduce availability of arachidonic acid without detrimental effect on the animal.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
Not applicable.
DETAILED DESCRIPTION OF THE INVENTION
Prostaglandins and leukotrienes are believed to cause gastrointestinal inflammation which increases tissue damage and negatively affects the ability of animals, particularly mammals and avians, to convert feed into body weight. Limiting the availability of the precursors for these lipid metabolites reduces gut wall thickening, alters animal feeding behavior and improves animal health.
When the gut encounters endotoxins, Phospholipase A
2
(PLA
2
) becomes active and an inflammatory response begins which can cause gut wall thickening and decreased weight gain. By limiting the production of lipid metabolites such as prostaglandin and leukotriene during normal food digestion, stimulation of intestinal smooth muscle is reduced, and more efficient feed conversion and bodily growth results. By limiting these lipid metabolites during gastrointestinal traumas, such as colitis and necrosis, inflammation is reduced and further tissue damage is avoided. The invention is preferably practiced on avian or mammalian animals. Preferred avian animals include chickens, ducks, turkeys, quail, and geese. Preferred mammalian animals include bovine, ovine, porcine, caprine, rodent and human animals.
In a preferred embodiment of the present invention, prostaglandin and leukotriene production is limited by decreasing the availability of arachidonate, a necessary precursor, by reducing or preventing arachidonate from being cleared from membrane phospholipids. One method for doing so involves interfering with phospholipase A
2
(PLA
2
), the enzyme that clears arachidonate from membrane phospholipids. By reducing or preventing arachidonate release, the pool of available prostaglandin and leukotriene precursors is necessarily reduced.
The applicant has determined that by reducing the available arachidonate, the levels of prostaglandins and leukotrienes are reduced. The strategy is preferably practiced by preventing arachidonate release. This can be preferably achieved by reducing or eliminating activity of the PLA
2
enzyme. The PLA
2
enzyme activity can be reduced using an anti-PLA
2
antibody which, without intending to limit the applicant, is believed to complex with the PLA
2
enzyme and thereby interfere with its phospholipase activity. Polyclonal or monoclonal anti-PLA
2
antibodies can be prepared or administered using any of various methods known in the art to produce an antib
Delacroix-Muirhei C.
Jones Dwayne C.
Quarles & Brady LLP
Wisconsin Alumni Research Foundation
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