Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector
Reexamination Certificate
1995-06-07
2001-10-16
Minnifield, Nita (Department: 1645)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
C424S185100, C424S193100, C424S194100, C424S198100, C530S850000, C530S300000, C530S313000, C530S326000, C530S327000, C530S328000, C530S329000, C530S810000, C530S827000, C530S852000, C530S853000, C530S854000, C514S002600, C514S800000, C930S110000, C930S130000
Reexamination Certificate
active
06303123
ABSTRACT:
BACKGROUND OF THE INVENTION
Gonadotropin Releasing Hormone (“GnRH”, also known as Luteinizing Hormone Releasing Hormone, or “LHRH”), is of central importance to the regulation of fertility. Johnson M., Everitt B.
Essential Reproduction,
3rd Edn. Blackwell Scientific Publications, 1988. In males and females, GnRH is released from the hypothalamus into the bloodstream and travels via the blood to the pituitary, where it induces the release of the gonadotropins, luteinizing hormone and follicle stimulating hormone, by gonadotrophs. These two gonadotropins, in turn, act upon the gonads, inducing steroidogenesis and gametogenesis. Steroids released from the gonads into the circulation subsequently act upon various tissues.
The gonadotropin hormonal cascade can be halted by neutralization of the biological activity of GnRH. Fraser H. M. Physiological Effects of Antibody to Leutenizing Hormone Releasing Hormone. In:
Physiological Effects of Immunity Against Reproductive Hormones
, Edwards and Johnson, Eds. Cambridge University Press, 1976. As a consequence of GnRH neutralization, the gonadotropins and gonadal steroids are not released into the blood and their biological activities are thereby eliminated. By eliminating the biological activity of GnRH, the hormonal regulation of fertility is interrupted and gametogenesis ceases. GnRH neutralization halts the production of gametes. GnRH neutralization is thus an effective means of contraception.
A number of important diseases are affected by gonadotropins and gonadal steroid hormones, particularly the gonadal steroids. Such diseases include breast cancer, uterine and other gynecological cancers, endometriosis, uterine fibroids, prostate cancer and benign prostatic hypertrophy, among others. Removal of the gonadal steroid hormonal stimuli for these diseases constitutes an important means of therapy. An effective method of accomplishing this is by neutralizing GnRH, the consequence of which is the elimination of gonadal steroids that induce and stimulate these diseases. McLachlan R. I., Healy D. L., Burger G. B. 1986. Clinical Aspects of LHRH Analogues in Gynaecology: a Review,
British Journal of Obstetrics and Gynaecology,
93:431-454. Conn P. M., Crowley W. F. 1991. Gonadotropin-Releasing Hormone and Its Analogs,
New England Journal of Medicine.
324:93-103. Filicori M., Flamigni C. 1988. GnRH Agonists and Antagonists, Current Clinical Status.
Drugs.
35:63-82.
One effective means of neutralizing GnRH is the induction or introduction of anti-GnRH antibodies in the host or patient. Such antibodies can be induced by active immunization with GnRH immunogens or by passive immunization by administering anti-GnRH antibodies. Fraser H. M. Physiological Effects of Antibody to Leutenizing Hormone Releasing Hormone. In:
Physiological Effects of Immunity Against Reproductive Hormones
, Edwards and Johnson, Eds. Cambridge University Press, 1976. Since anti-GnRH antibodies can neutralize the biological activity of GnRH, immunization constitutes an important approach towards treating diseases dependent upon gonadal steroids and other reproductive hormones as well as a means to regulate mammalian fertility.
GnRH has the same amino acid sequence in all mammals (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-GlyNH
2
) (SEQ ID NO: 1 in the Sequence Listing), thus a single immunogen would be effective in all mammalian species, including humans. Active immunization against GnRH, however, has not been practicable due to deficiencies associated with the GnRH immunogens. The prior art anti-GnRH immunogens are not of sufficient potency, and therefore must be administered repeatedly to induce effective levels of anti-GnRH antibodies. In addition, they have not proven to be reliable, in terms of inducing anti-GnRH antibodies in an acceptable portion of the immunized population.
SUMMARY OF THE INVENTION
The present invention concerns methods for the treatment of gonadotropin and gonadal steroid hormone-dependent cancers such as breast, uterine, endometrial, prostatic cancers, and other hormone-dependent disorders such as, endometriosis, uterine fibroids, benign prostatic hypertrophy, etc. The methods comprise the administration to a patient of the inventive immunogens against GnRH which elicit a sufficient titer of anti-GnRH antibodies in the patient to physiologically neutralize so as to limit the cancer-trophic hormone levels in the patient. The physiological neutralization of GnRH inhibits the release of gonadal hormones and therefore, arrests or inhibits tumor growth. Since the methods of the invention inhibit the release of estrogen, thereby inhibiting the growth of the estrogen-dependent tumor cells, it is particularly suited for the treatment of estrogen related breast cancers.
The improved immunogens against GnRH of the present invention induce neutralizing titers of anti-GnRH antibodies in response to a single administration of the immunogen in all of the immunized populations that we have studied. The immunogens of the invention may to be used to treat steroid hormone-dependent diseases and may also be used as immunocontraceptives to regulate fertility.
The immunogens comprise peptides composed of two functional regions: the immunomimic region and a spacer region. The function of the immunomimic which immunologically crossreacts with GnRH is to induce antibodies that bind to the targeted hormone. The spacer element of the peptide serves as a link through which the immunomimic is attached to an immunological carrier, such as diphtheria toxoid (“DT”) and also affects the immune response generated by the vaccinated mammal against the immunomimic. For example, in a specific embodiment of the invention, the immunogen peptide has the sequence: pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-Arg-Pro-Pro-Pro-Pro-Cys (SEQ ID NO: 2 in the Sequence Listing). In this (“GnRH(1-10)-Arg10”) peptide, the sequence pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly- (SEQ ID NO: 3 in the Sequence Listing), comprises the immunomimic of GnRH. The remainder of the peptide's sequence, -Arg-Pro-Pro-Pro-Pro-Cys (SEQ ID NO: 4 in the Sequence Listing), constitutes the spacer, which is attached to amino acid number 10 of the GnRH immunomimic.
In one embodiment of the invention, the method of treatment of the hormone-dependent breast cancer comprises passive immunization in which antibodies against GnRH are administered to the patient in a sufficient concentration to reduce free circulating GnRH levels. The anti-GnRH antibodies by binding to GnRH inhibit the release of GnRH-induced pituitary gonadotropins, i.e., Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH) from the pituicytes and therefore, inhibit the release of gonadal hormones. In a preferred embodiment of this aspect of the invention, the anti-GnRH antibodies for human therapy are humanized or human antibodies which may be produced by methods well known to those of ordinary skill in the art. The immunogens induce the inhibition of the release of the gonadal hormones such as estrogen thereby inhibiting the growth of hormone-dependent tumor cells. Specifically, in an estrogen-dependent breast tumor, the administration of the antibodies leads to the inhibition of the release of estrogen, thereby arresting or slowing the growth of the estrogen-dependent tumor cell.
In another embodiment, the invention concerns a method for the treatment of hormone-dependent breast cancer by active immunization, comprising administering to a patient an immunogen or a pharmaceutical composition containing an immunogen which comprises peptide immunomimics of GnRH which are associated with spacer sequences and coupled to immunological carriers, such as DT. In this method of immunization against breast cancer, the immunogen is capable of inducing an immune response in which the patient produces antibodies at a titer sufficient to neutralize the physiological function the patient's own GnRH. The neutralization of GnRH by the binding of the anti-GnRH antibodies to GnRH in the patient leads to the inhibition of the release of gonadal hormones, i
Grimes Stephen
Scibienski Robert
Aphton Corporation
Minnifield Nita
White & Case LLP
LandOfFree
Methods for the treatment of hormone-dependent tumors with... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Methods for the treatment of hormone-dependent tumors with..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Methods for the treatment of hormone-dependent tumors with... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2610911