Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Food or edible as carrier for pharmaceutical
Reexamination Certificate
2001-07-16
2004-05-18
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Food or edible as carrier for pharmaceutical
C424S400000, C424S489000, C424S499000
Reexamination Certificate
active
06737076
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a hypoallergenic composition containing specific tolerogenic peptides of proteins, wherein the composition can induce oral tolerance to the native proteins. It also relates to the use of tolerogenic peptides of milk protein for the preparation of a composition inducing immunological tolerance to milk proteins.
BACKGROUND OF THE INVENTION
During the common process of nutrition, dietary proteins are presented to the immune system via the gut, followed by an immune unresponsiveness to the ingested nutrients. This vital phenomenon, called oral tolerance, is efficient for the large majority of people. If oral tolerance fails, food allergy occurs, requiring the strict avoidance of the incriminated food.
Targeted food avoidance represents a hard task for adult patients with food allergy. For example, to strictly remove cow's milk from the diet of allergic infants might be even more difficult, especially if breastfeeding is not possible or desired.
The allergies to cow's milk and to the formulas containing cow's milk adapted to the needs of infants are due to the fact that the proteins of cow's milk differ from the proteins of mother's milk and can constitute allergens. Among whey proteins, &bgr;-lactoglobulin is the major component and is a strong allergen.
Besides breastfeeding, the primary recommendation for prevention, hypoallergenic formulae are systematically prescribed to “at risk” newborns, namely asymptomatic infants with atopic parents.
In contrast to adapted formulae, cow's milk proteins have been hydrolyzed in hypoallergenic formulae, to decrease the potential allergenicity. This approach has been demonstrated to be efficient in order to prevent sensitization by native proteins present in the adapted formulae.
Thus, in U.S. Pat. No. 4,293,571 a protein hydrolysate was prepared by pancreatic hydrolysis, coagulation of non-hydrolyzed proteins by a heat treatment and ultrafiltration to eliminate the coagulated residual proteins and the macropeptides that could constitute allergens. Also, U.S. Pat. No. 5,039,532 provides an improved process for the preparation of a hydrolysate of animal milk proteins substantially reduced in allergens, in which a whey product was subjected to enzymatic hydrolysis.
Two different types of hypoallergenic formulae are proposed to high-risk babies: partially and extensively hydrolyzed formulae, differentiated by the extent of hydrolysis of the native proteins. But as is clear from the art cited above, the primary focus to date in dealing with allergies to cow's milk has been to find preparations that will not induce an allergic response, i.e. to provide non-allergenic formulations. Nonetheless, while such formulations have permitted a person allergic to cow's milk to avoid an allergic response, they do not solve the problem which is to enable a person to drink unaltered milk products.
More recently, it has been investigated that partially hydrolyzed milk formulations are not only of reduced allergenicity but can induce immunological tolerance to milk proteins (see, e.g., European patent application 0 827 679). Extensively hydrolyzed formulae are specially designed for treating patients allergic to cow's milk proteins but their ability to induced long-term oral tolerance is questioned.
Thus, European patent application 0 629 350 discloses the use of non-allergenic whey protein hydrolysates which are said to be capable of inducing cow's milk protein tolerance. Although this patent application indicates that whey protein hydrolysates substantially free of allergenic proteins could be used to induce cow's milk protein tolerance in children at risk of cow's milk allergy, the present inventors found on analyzing other non-allergenic whey protein hydrolysates that non-allergenicity did not necessarily translate into the ability to induce cow's milk protein tolerance. Indeed, some of the formulations exhibiting the highest degree of non-allergenicity were found to be unsuitable for inducing cow's milk protein tolerance.
Although Lo, C. W. and Kleiman, R. E. (American Journal of Clinical Nutrition 1996, 63 (4), 646S-650S) suggest that infant formula containing tolerogenic peptides could be used for treating allergic diseases or suppressing the development of autoimmune disorders, it is clear that the art lacked the information to provide formulae that would be the most suitable for tolerance induction The present invention now overcomes the shortcomings of the art.
SUMMARY OF THE INVENTION
This invention relates to a hypoallergenic composition for the induction of protein tolerance in at risk individuals of protein allergy. The composition contains (i) a “non-allergenic” extensively hydrolyzed proteins basis and/or (ii) a free amino acid basis, and comprises as the active ingredient at least one tolerogenic peptide of the allergenic protein.
In a preferred embodiment, the tolerogenic peptide is present in the form of (i) one or more isolated tolerogenic peptidic fractions of hydrolysis of proteinaceous material containing the allergenic protein, and/or (ii) one or more synthetically prepared tolerogenic peptides.
This composition also contains a source of nitrogen which may provide 7 to 25% of the total energy, a source of carbohydrates which may provide at least 28 to 66% of the total energy, a source of lipids which may provide at least 25 to 60% of the total energy and at least one tolerogenic peptide of the different proteins.
A major advantage of this composition is to induce oral tolerance in “at risk” individuals, in order to avoid eventual sensitization by use of native tolerogens. Moreover, the tolerogenic peptides derived from protein hydrolysis offer both hypoallergenic and tolerogenic properties and induce oral tolerance at the humoral and cellular levels.
This composition is particularly intended for individuals at risk of milk protein allergy.
Another aspect of the present invention is the use of tolerogenic peptides of milk proteins for the preparation of a hypoallergenic composition intended for mammals susceptible to cow's milk allergy.
In a preferred embodiment, tolerogenic peptides are from milk origin and particularly from &bgr;-Lactoglobulin (&bgr;-LG), &agr;-lactalbumin, bovin serum albumin or casein origin.
For the preparation of the composition, tolerogenic peptides may be used in the form of peptidic fractions containing the following peptides: H
2
N-I-D-A-L-N-E-N-K-COOH, H
2
N-V-L-V-L-D-T-D-Y-K,-K-COOH or H
2
N-T-P-E-V-D-D-E-A-L-E-K-F-D-K-COOH from &bgr;-Lactoglobulin.
In another aspect, the invention provides a method for the preparation of tolerogenic peptides useful in the induction of protein tolerance in at risk individuals to protein allergy, wherein:
(i) a proteinaceous material containing the allergenic protein is hydrolyzed to a degree of hydrolysis of about 10 to 50%;
(ii) then treated to inactivate residual enzyme activity; and
(iii) the protein hydrolysate solution is clarified and submitted to precipitation treatment or passed into a chromatography column filled with appropriated resin to extract the tolerogenic peptidic fractions.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In the present invention, the term tolerance is to be understood as a state of specific immunological unresponsiveness. Both humoral (antibodies) and cell-mediated (lymphocyte . . . ) pathways of the immune response may be suppressed by tolerance induction. A breakdown of oral tolerance is considered to be the underlying cause of food allergy.
The term “allergen” is to be understood as a protein or macropeptide capable of initiating allergic reactions in humans, particularly at risk infants or nurslings. Infants are considered being “at risk” of protein allergy when either one or two parents or one sibling is atopic.
The term “tolerogenic peptide” is to be understood as a proteic fragment or fragments corresponding to parts of the native protein, sized from 200 to 6000 Daltons (“Da”), corresponding to about 3 to 50 amin
Bovetto Lionel
Fritsche Rodolphe
Maynard Francoise
Pecquet Sophie
Evans Charesse
Nestec S.A.
Page Thurman K.
Winston & Strawn LLP
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