Methods for altering fertility

Abstract

The present invention relates to methods for enhancing fertility by reducing the activities and / or levels of circulating glycoprotein hormones having lutropin (LH) activity. The molecules of the invention are antibodies or other binding agents that reduce the biological activities of LH. The present invention also relates to novel methods for devising and / or selecting antibodies to specific portions of proteins including LH and human chorionic gonadotropin (hCG) to permit their biological activities to be reduced to desired degrees. The present invention also relates to the preparation of single subunit gonadotropins and gonadotropin antagonists for use in stimulating and inhibiting fertility and for controlling ovarian hyperstimulation. In a preferred embodiment, the present invention pertains to a method for stimulating fertility in mammals by reducing the activity of glycoprotein hormones having luteinizing hormone activity in circulation and thereby stimulating the production of follicle stimulating hormone which comprises administering to the mammal a therapeutically effective amount of a binding agent that binds luteinizing hormone.

Description

BACKGROUND OF THE INVENTION [0001] 1. Field of the Invention [0002] The present invention relates to methods for enhancing fertility by reducing the activities and / or levels of circulating glycoprotein hormones having lutropin (LH) activity. The molecules of the invention are antibodies or other binding agents that reduce the biological activities of LH. The present invention also relates to novel methods for devising and / or selecting antibodies to specific portions of proteins including LH and human chorionic gonadotropin (hCG) to permit their biological activities to be reduced to desired degrees. The present invention further relates to novel glycoprotein hormone agonists and antagonists that reduce the activities of hormones with LH activities and / or increase the activities of hormones with follitropin activity. [0003] 2. Description of the Background [0004] The disclosures referred to herein to illustrate the background of the invention and to provide additional detail with res...

AI Technical Summary

Benefits of technology

This approach allows for the reduction of LH activity to enhance fertility by increasing FSH levels, reducing the risk of ovarian hyperstimulation and requiring fewer treatments, while also providing a specific method to inhibit fertility by targeting hCG, thus avoiding the side effects associated with other hormone neutralization.

Problems solved by technology

Lack of sufficient FSH, LH, or hCG at appropriate times results in infertility or termination of pregnancy.

Excessive amounts of these hormones can result in premature puberty or hyperstimulation of the gonads.

Immunoneutralization of FSH leads to a diminution in spermatogenesis and a loss in fertility.

In males, LH is required for puberty and, in its absence, there is a failure to acquire the sexual attributes and fertility of an adult.

Unfortunately, since the negative effects of estradiol on FSH secretion are partly responsible for controlling the number of follicles that develop to the point of ovulation, disruption of the normal estrogen-FSH negative feedback loop can result in inappropriate numbers of ova being shed.

Thus, even a massive excess of either antibody sufficient to bind virtually all the free hCG or LH in the assay is incapable of preventing a response to either hormone when the concentrations of the hormone-antibody complexes exceed a threshold level.

Thus, one would not expect that this approach to fertility would be successful.

Glycoprotein hormones lacking carbohydrate residues have impaired abilities to elicit a biological response.

Deglycosylated gonadotropins have been found to have short biological half-lives and were found not to be useful for their original intended use, namely to inhibit fertility by reducing luteal progesterone synthesis and causing abortion.

Due to the action of hCG in maintaining pregnancy, treatments that lead to diminished hCG secretion or activity would also be expected to cause infertility.

This is because treatments that neutralized hLH or hFSH would cause cessation of ovarian function and hasten the onset of problems associated with menopause.

Unfortunately, development of the vaccine has been hampered by the structural homologies between all the glycoprotein hormones.

Unfortunately, neutralization of LH or FSH would also result in cessation of normal menstrual cycles and the loss of estrogen production that is associated with fertility in women.

Termination of ovarian function would be likely to result in premature development of osteoporosis and other problems associated with menopause.

Inhibition of thyroid function would lead to hypothyroidism.

Similarities in the structures of hCG and hLH have made it particularly difficult to design an appropriate immunogen that does not generate crossreacting antibodies.

However, this region is not very antigenic.

Unfortunately, most of these immunogens are not very effective and a better immunogen is needed to make this method practical.

Since anti-α-subunit antibodies are often capable of blocking the activities of the hormones (22), an immunogen which induced a response to the α-subunit is likely to have unwanted side effects.

Unfortunately, the antibodies that are produced to synthetic CTP peptides do not bind with high affinity to hCG.

The problem with using this loop structure is that the antibodies that are produced are often of low affinity.

While the hormone has been crystallized and a crystal structure would be valuable in determining the types of immunogens that would give a high titer immune response to particular parts of the molecule, difficulties in solving the crystal structure have precluded this approach.

Thus, at the present state of the knowledge of hCG structure, there is no good method that could be used to predict the type of immunogen that would be most effective.

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