Immunogenic LHRH peptide constructs and synthetic universal immu

Details Immunogenic LHRH peptide constructs and synthetic universal immu Immunogenic LHRH peptide constructs and synthetic universal immu

1995-12-26

1998-06-02

Smith, Lynette F.

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Hormone or other secreted growth regulatory factor,...

4241851, 4242271, 514841, 514843, A61K 3900, A61K 3929

Patent

active

057595518

DESCRIPTION:

BRIEF SUMMARY
This invention relates to immunogenic luteinizing hormone releasing hormone (LHRH) peptides that lead to functional suppression of LHRH levels in males or females. When male rats are immunized with these peptides, serum testosterone drops and androgen-dependent organs atrophy significantly. These peptides are useful for inducing infertility and for treating prostatic hyperplasia, androgen-dependent carcinoma, prostatic carcinoma and testicular carcinoma in males. In females, the peptides are useful for treating endometriosis, benign uterine tumors, recurrent functional ovarian cysts and (severe) premenstrual syndrome as well as prevention or treatment of estrogen-dependent breast cancer. The subject peptides contain a helper T cell epitope (Th epitope) and have LHRH at the C terminus. The helper T cell epitope aids in stimulating the immune response against LHRH. The peptides, optionally, contain an invasin domain which acts as a general immune stimulator.
In another aspect this invention relates to immunogenic synthetic peptides having an invasin domain, a helper T cell epitope and a peptide hapten and methods of using these peptides to treat disease or provide protective immunity. The peptide haptens of the invention include LHRH, amylin, gastrin, gastrin releasing peptide, IgE CH4 peptides, Chlamydia MOMP peptides, HIV V3 peptides and Plasmodium berghei peptides.
Prostate cancer is the third leading cause of death in men and the most common malignancy in men over the age of 70 years. The number of new prostate cancer cases has risen steadily over the past 20 years, with the expectation that more than 4 million men over the age of 75 may develop al. (1985) in Cancer Principles and Practice of Oncology. Vol. 9 (DeVita et al., eds.) J. B. Lippincott Company, Philadelphia, Pa., pp. 1023-48; Chodak et al. (1990) Current Concepts in Prostate Cancer Diagnosis and Management, 26th Annual Meeting, American Society of Clinical Oncology. Unfortunately, at the time of diagnosis about 40-50% of the patients with newly diagnosed prostate cancer will have advanced disease (stage D), with 4:15). Consequently, the therapies developed to combat this disease should demonstrate efficacy as rapidly as possible.
The classical treatment for advanced prostate cancer has been surgical orchiectomy, i.e. castration, developed by Huggins and others in the early reduces serum testosterone by 95%, causes measurable tumor regression in approximately 45% of patients, and disease stabilization in an additional 40% of patients. At least temporary stabilization of advanced prostatic disease, including improvement of urinary tract symptoms and reduction of pain, occurs in about 70% of patients (Klein (1979) N. Engl. J. Med. 300:824-33!. While such treatments are effective, particularly when combined with estrogen therapy, the associated psychological trauma is unacceptable to some patients.
Over 95% of testosterone production originates in the testes. Testosterone production in the Leydig cells of the testes is controlled by pituitary secretion of luteinizing hormone (LH). The secretion of LH together with follicle stimulating hormone (FSH), in turn is controlled by the pulsatile Textbook of Endocrinology (Williams, ed.) Saunders, Philadelphia, Pa., pp. 323-367).
Attempts to block LHRH, to reduce testosterone effect on androgen-dependent organs, e.g. prostate, or to block other parts of this pathway have provided therapeutic alternative treatments for prostate cancer, including treatment with estrogens or LHRH analogs. Unfortunately, therapeutic doses of estrogens can cause significant side effects such as cardiovascular (1975) Can. Chem. Rep. 59:225-7!. Treatment with LHRH analogs, such as Leuprolide or goserelin, causes eventual decline of serum testosterone; however, the associated initial rise of serum LH and FSH levels (450 and 250 per cent, respectively), leads to a painful condition known as the "flare up phenomena" in which a temporary increase in serum testosterone and other symptoms occur (Crawford et al. (1991) Urol. Clin. N.A.

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