Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-03-22
2001-09-04
Davenport, Avis M. (Department: 1654)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S010100, C514S011400, C530S300000, C530S313000, C530S326000, C530S402000, C424S185100
Reexamination Certificate
active
06284733
ABSTRACT:
This invention relates to a peptide suitable for producing a vaccine effective against the Luteinising Hormone Releasing Hormone (LHRH, also referred to as Gonadotrophin Releasing Hormone, GnRH). The invention further relates to immunogenic compositions and vaccines or medicinal preparations (vaccines and pharmaceuticals) based on such a peptide and the use of such a vaccine or medicinal preparation in a method of immunizing a mammal against LHRH and thereby influencing reproductive or behavioral characteristics of that mammal and a method of improving the meat quality of pigs.
LHRH is a small 10 amino acid long peptide (decapeptide) from the hypothalamus. The amino acid sequence (with, as usual, the amino terminal amino acid to the left and the carboxy terminal amino acid to the right) of LHRH is according to the formula in which the amino acids are coded with the three-letter code: pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH
2
, or in the one letter code according to the formula: #E H W S Y G L R P G@, #E is pyroglutamic acid and G@ is glycine amide.
LHRH acts at the hypophysis to cause an increase in release of biologically active FSH (follicle-stimulating hormone) and LH (luteinising hormone) in the blood which, in turn, stimulate the development of the testes in the growing male animal and the synthesis of testicular steroids. In the growing female animal the development of the ovaries is stimulated and therein follicle development, synthesis of ovarian steroids and ovulation.
It is known that LHRH, if coupled to a carrier protein, can be used to vaccinate animals. Such a vaccination can be carried out for different reasons which are all connected with the natural function of the LHRH. As is known, a drastic reduction of LH and FSH in the blood inhibits the production of testicular steroids or androgens and sperm in the testis of the male and the formation of ovarian steroids or progestagens and estrogens and follicle maturation in the ovary of the female. Such a reduction of the amounts of androgens, progestagens and estrogens in the blood to a level comparable to the level obtainable by removing the testes or ovaries via castration can be achieved by effective immunization of the animal against LHRH. In male animals, in many cases, the testes then appear to develop slowly or not at all (no synthesis of androgens (male steroid hormones) and no formation of spermatozoa) and in female animals, the activity of the ovaria appears to diminish (synthesis of estrogens and progestagens (female steroid hormones), ripening of follicles and ovulation are inhibited).
In veterinary medicine, 100% effective immunisation against LHRH could be used for the sterilisation of, e.g., small domestic animals, such as male and female cats and dogs, or for the treatment of aggressiveness in male dogs and bulls, simply by vaccination instead of by drastic surgery, such as castration or ovariectomy. Other conceivable reasons for immunisation against LHRH are to prevent heat in female animals, such as dogs, cats and cows, and restlessness in male animals being fattened for slaughter. In human health care, immunisation against LHRH can be used in the treatment of prostate cancer and breast cancer and, if required, in the treatment of some forms of pituitary carcinoma.
Another use of a vaccine against LHRH is in the field of stock breeding, particularly the fattening of pigs for slaughter. The meat of male, sexually mature pigs (boars) has a typical odour, the so-called boar taint or boar odour. In the sexually mature pig, in the testes, many C19-&Dgr;16 steroids are formed which are stored in the fat tissue of the animal (Patterson, J. Sci. Food Agric. 19, 31-38 (1968); Brooks en Pearson, J. Anim. Sci. 62, 632-645 (1986); Claus, Zeitschrift. Tierzüchtg. Züchtungsbiol. 93, 38-47 (1976); Claus,. Acta Endocrinol. (Copenh.) 91, Suppl. 225, 432-433 (1979)). These steroids are mainly responsible for the formation of the disagreable urine-like odour when the meat is heated (Fuchs, Swedish J. Agric. Res. 1, 233-237 (1971); Bonneau, Livest. Prod. Sci. 9, 687-705 (1982)). Owing to this unpleasant odour, meat of male sexually mature pigs is hardly, if at all, suitable for consumption and unfit for export. Because about 10% of the maple slaughter pigs are already sexually mature before the slaughter time, this potentially entails a great loss for the pig farming industry.
In order to control and prevent these losses, nearly all male piglets are castrated when they are young with a surgical procedure that is generally executed without any form of anaesthesia. Apart from the animal unfriendly aspect of such a castration, castration also leads to infections, growth inhibition, and a final meat quality inferior to that of an intact animal (at least as long as that intact animal has not yet developed boar taint) (Walstra, Livest. Prod.Sci. 1, 187-96 (1974)).
An animal friendly alternative which, in addition, benefits meat quality, consists in the reduction of the LHRH concentration at the pituitary of the young animal by means of immunisation against LHRH. This reduction in LHRH levels leads to a reduction in the concentrations of biologically active FSH and LH which, in turn, will inhibit development of the testes in the growing animals and inhibit the synthesis of testicular steroids among which the C19-&Dgr;16 steroids. Animal unfriendly castration becomes unnecessary: infections and growth inhibition are being prevented while the ultimate meat quality certainly is not less than after castration. In addition, this method prevents the occurrence of boar taint in male pigs before slaughter time.
However, a strict requirement for a good vaccine against boar taint is that in all pigs development of the testes is being delayed to such an extent that in no case boar taint will occur before slaughter time, even not when tested in a very large population of pigs. The known vaccine preparations do not meet this requirement.
In the existing literature and previous patent applications regarding the anti-fertility properties of vaccines against LHRH, the results of vaccinations often appear to be variable, for instance, some vaccinated animals hardly, if at all, respond to the vaccination, or large doses in commercially unacceptable adjuvants are needed for the desired effect (Chaffaux et al., Recueil de Médicine Vétérinaire 161 (2), 133-145 (1985); Caraty et al., C. R. Acad. Sc. Paris, t. 303, Séerie III, No. 16, 673-676 (1986); Falvo et al.; J. Anim. Sci. 63, 986-994 (1986); Goubau et al., Domest. Anim. Endocrinol. 6, 339-347 (1989a); Goubau et al., Theriogenology 32, 557-567 (1989b); Hoskinson et al, Austr. J. Biotech; 4, 166-170 (1990); Bonneau et al., J. Anim. Sci. 72, 14-20 (1994); U.S. Pat. No. 4,608,251; Int. patent appl. WO 88205109). According to the literature data, it is not possible, using vaccination against LHRH, to block testis development in each individually immunized pig at a sufficiently early stage to entirely prevent the problem of boar odor. The percentage of success appears to lay between 20 and 80%. This is insufficient and renders the present generation LHRH-vaccines useless for farming practice.
The difficulty in preparing this type of vaccines probably is caused by the phenomenon of “tolerance”. “Self” substances such as hormones are not recognized but are indeed tolerated by the immune system. Normally, no antibodies are being elicited against self substances. A successful vaccine therefore needs to use a substance sufficiently like the hormone but at the same time sufficiently “foreign” to induce production of antibodies. Because these are mutually exclusive conditions, it was not certain, until recently, if such substances could be prepared at all. One attempt to produce LHRH-like peptide vaccines consisted of the replacement of Gly at position 6 of the LHRH decapeptide by a dextrorotary amino acid (D-Tryp; Chaffaux et al., Recueil de Médicine Vétérinaire 161 (2), 133-145, 1985). It was, however, demonstrated that a vaccine preparation containing this modified LHRH-pepti
Meloen Robert Hans
Oonk Hendrica Berendina
Davenport Avis M.
DLO Instituut Voor Dierhouderij En Diergezondheid
TraskBritt
LandOfFree
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