Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...
Reexamination Certificate
2000-09-12
2004-07-13
Eyler, Yvonne (Department: 1647)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
C530S398000, C530S399000, C530S402000, C530S403000, C514S012200, C514S013800
Reexamination Certificate
active
06761890
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a peptide suitable for eliciting an immune response against forms of Gonadotropine Releasing Hormone (GnRH) also referred to as Luteinizing Hormone Releasing Hormone (LHRH). The invention further relates to immunogenic compositions and vaccines, pharmaceuticals, and other medicinal preparations based on such a peptide. The invention further relates to the use of such a vaccine or medicinal preparation in a method of immunizing a mammal against GnRH to influence reproductive or behavioral characteristics of that mammal and in a method of improving the carcass quality of pigs. The invention also relates to a peptide suitable for eliciting a selective immunogenic response against GnRH-I or GnRH-II. Further the invention relates to antibodies against GnRH-I, to compositions comprising these antibodies and to the use of the peptides in pharmaceutical compositions or in the preparation for a medicament for the treatment of prostate cancer.
2. State of the Art
GnRH-I (in the literature generally depicted as GnRH) is a small 10 amino acid long peptide (decapeptide) from the hypothalamus. The amino acid sequence of GnRH-I (SEQ ID NO:1) can be represented by the following three-letter code:
pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH
2
or the corresponding one letter code where pE is pyroglutamic acid and # is amide:
pE H W S Y G L R P G# SEQ ID NO:1
GnRH-I acts at the hypophysis to cause an increase in release of biologically active Follicle-Stimulating Hormone (FSH) and Luteinizing Hormone (LH) in the blood, which in turn stimulate the development of the tests in the growing made animal and the synthesis of male steroids. In the growing female animal the development of the ovaries is stimulated, as is the development of follicles within the ovary, synthesis of female steroids, and ovulation.
It is known that GnRH-I, if coupled to a carrier protein, can be used to vaccinate animals. Such a vaccination can be carried out for various reasons, all of which are connected with the natural function of the GnRH-I. As is known, a drastic reduction of LH and/or FSH in the blood inhibits the production of male steroids or androgens and sperm in the testis of the male and the formation of female steroids or progestagens and estrogens and follicle maturation in the ovary of the female. Such a reduction in the amounts of androgens, progestagens and estrogens in the blood, to a level comparable to that obtainable by removing the testes or ovaries via castration, can be achieved by effective immunization of the animal against GnRH-I. In male animals, in many cases the testes then appear to develop slowly or not at all, with no synthesis of androgens (male steroid hormones) and no formation of spermatozoa. In female animals the activity of the ovaria appears to diminish, with no synthesis of estrogens and progestagens (female steroid hormones), and inhibition of ripening of follicles and ovulation.
Recently it was reported that a second form of GnRH (GnRH-II) is present in primate brain (Lescheid et al. Endocrinol. 138(1997) 5618-5629) and a gene for this second GnRH molecule was cloned from a human genomic library (GnRH-II, amino acid sequence pEHWSHGWYPG# (SEQ ID NO:2)) (White et al., PNAS USA 95 (1998) 305-309). Mammalian GnRH-I (SEQ ID NO 1) is hardly expressed outside the brain. A few exceptions are known in this respect. GnRH I is present in the endometrium of women with a menstrual cycle (Casan et al. Fertil, Sateril, 1998, 70, 102-106) and is expressed during pregnancy in the human placenta (Kelly et al. DNA cell Biol. 1991, 10, 411-421). GnRH and mRNA was found in ovary, testis, thymus, placenta and hypothalamus of the rat (Oikawa et al., Endocrinology, 1990, 127, 2350-2356). Expression of GnRH was detected in immune tissue (spleen, thymus and lymphocytes) of pigs (Weesner et al., Life Sci, 1997, 61, 1643-1649).
GnRH-II is expressed in many tissues outside the brain, and is found is especially high concentrations in the kidneys, bone marrow and prostate. The presence of GnRH-II in diverse tissues other than the brain suggests that GnRH-II may have multiple functions. In addition, the strictly conserved structure of the GnRH-II peptide throughout diverse vertebrate species suggests that this neuropeptide possesses vital bioactivites. Until now, however, the functions of GnRH-II have been practically unknown. Several types of differential lymphocytes, such as T- and B-lymphocytes and mast cells, produce GnRH and GnRH-like peptides. Significant numbers of the latter cell type are present in kidney, bone marrow and prostate, perhaps contributing to the high GnRH-II expression in these tissues. GnRH II seems less involved in reproduction as compared to GnRH-I. In the hypogonadal mouse, mouse which lack the GnRH-I gene, GnRH-II producing cells are present in the same distribution as in normal mouse, but this is not sufficient to cause normal gonadal development in these mouse (Chen et al. FEBS Letters 435 (1998) 199-203). However, macaques in luteal phase of the menstrual cycle showed a marked increase in plasma luteinizing hormone concentrations after intravenous administration of GnRH-II, but this increase could not be induced during the mid follicular phase (Lescheid et al., Endocrinol. 138 (1997) 5618-5629.)
BRIEF SUMMARY OF THE INVENTION
The invention now provides the insight that by providing peptide sequences that allow discrimination between the different types of GnRH, more adequate and efficient use can be made of the variation or different in immunological response to the different types of GnRH. More particularly, the invention provides the insight that improvements in the efficiency and selectivity of the vaccines against GnRH-I can be achieved.
Immunization against GnRH-I is effective in neutralizing GnRH-I and results in reduced genadotropin levels and blocking of gonadal steroid synthesis. However, nothing in known about any physiological effects of the antibodies raised against GnRH-I on the function of GnRH-II. As GnRH-II is mainly synthesized and secreted in the kidneys antibodies raised against GnRH-I that cross-react with GnRH-II may affect kidney function. To obviate possible side effects of GmRH-I immunization on kidney function it would be desirable to direct the antigenic response of an immunocastration vaccine specifically toward GnRH-I and to avoid possible harmful side-effects due to neutralization of non-gonadal GnRH-II.
If the reproductive capacity alone, often with its accompanying sexual behavior, of a species needs to be annulled, it would be preferred to aim at an immunocastration vaccine specifically neutralizing GnRH-I. Hence the desired to come to a selective immunization against Gonadotropine Releasing Hormone(s), preferably selective against GnRH-I.
In veterinary medicine, 100% effective immunization against GnRH-I could be used for the sterilization 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 immunization against GnRH-I are to prevent heat in female animals, such as dogs, cats and cows, and restlessness in male animals being fattened by slaughter.
In human health care immunization against GnRH-I and/or GnRH-II can be used in the treatment of prostatic cancer and breast cancer and, if required, in the treatment of some forms of pituitary carcinoma. In the case of prostate cancer it might be more desirable to neutralize both GnRH-I and GnRH-II, as the latter isoform is also highly expressed in prostate tissue.
Another use of a vaccine against GnRH-I is in the field of stock breeding, particularly the fattening of pigs of slaughter. The meat of male, sexually mature pigs (boars) has a typical odor, the so-called boar taint or boar odor. In the testes of the sexually mature pig, many C19-delta-16 steroids are formed which are stored in the fat tissue of the
Meloen Robert Hans
Oonk Hendrica Berendina
DeBerry Regine M.
Eyler Yvonne
Pepscan Systems B.V.
TraskBritt
LandOfFree
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