Composition and method for regulation of body weight and associated conditions

Abstract

Methods for regulating body weight and / or regulating weight gain are provided herein. The methods are useful, for instance, for treating or preventing obesity. Specifically, methods of administering varying levels of various alpha melanocyte stimulating hormone (α-MSH) analog compounds to an animal are provided for reducing body weight and / or reducing the rate of body weight gain.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation of application Ser. No. 09 / 458,580, filed Dec. 9, 1999 (pending), which is hereby incorporated by reference herein and which claims priority under U.S.C. § 119(e) from: U.S. Provisional Application Nos. 60 / 111,581, filed Dec. 9, 1998; 60 / 146,306, filed Jul. 29, 1999; 60 / 146,305, filed Jul. 29, 1999; 60 / 146,304, filed Jul. 29, 1999; 60 / 146,303, filed Jul. 29, 1999; 60 / 146,302, filed Jul. 29, 1999; 60 / 146,301, filed Jul. 29, 1999; 60 / 146,300, filed Jul. 29, 1999; and 60 / 146,299, filed Jul. 29, 1999. Each of the above-referenced provisional patent applications is incorporated herein by reference in its entirety.FIELD OF THE INVENTION [0002] The present invention relates to a composition and method for regulation of body weight and conditions related thereto, and particularly, to uses of proopiomelanocortin (POMC) peptides and analogs thereof to control body weight and conditions related thereto. BACKGROUN...

AI Technical Summary

Benefits of technology

[0144] As discussed above, it is an advantage of the method of the present invention that the effect of the POMC peptide administration is substantially restricted to the periphery, so that body weight and / or mass of an animal can be regulated in the absence of significantly affecting the appetite of the animal. As the present inventors have discovered, it is not necessary to have a significant, if any, primary effect on appetite to affect weight loss in an anima. As will be discussed in detail below, this advantage of the present invention is most easily achieved by administration of the POMC compound peripherally (i.e., by a route that does not deliver the compound directly or preferentially to the central nervous system and especially the brain). When a POMC compound is administered peripherally in an amount effective to act on peripheral receptors while mitigating effects on central receptors (e.g., the molar concentration of a melanocortin agonist that would be necessary to effect a transient decrease in food intake via the central nervous system and the melanocortin 4-receptor when delivered peripherally is at least one hundred-fold higher than that required to accomplish weight reduction via peripheral receptors, and is likely to be toxic), no additional modification of the POMC peptide is necessary. However, in one embodiment of the invention, the potential for effects on the central nervous system can be further minimized by selecting POMC compounds that preferentially bind to and / or activate / inhibit the peripheral melanocortin receptors as compared to the central melanocortin receptors, and particularly melanocortin 4-receptor (MC4-R). In one embodiment of the present invention, the administration of the POMC compound is insufficient to cause a statistically significant change in the appetite of the animal as compared to the appetite of the animal prior to administration of the compound. According to the present invention, “insufficient to substantially change” or “insufficient to statistically significantly change” the appetite of an animal refers to an inability to produce a measurable change in the appetite of an animal that is statistically different than the measured appetite of the animal prior to a treatment. Appetite changes can be measured, for example, by monitoring food intake and for humans, can include objective or subjective analysis of appetite changes.

[0145] In one embodiment, wherein decrease in body weight and / or mass is the goal, a preferred POMC compound: (1) binds to an MC2-R and / or MC5-R with a higher affinity (or avidity) than to an MC4-R; and / or (2) activates an MC2-R and / or MC5-R to a greater degree or preferentially as compared to an MC4-R. In another embodiment, a preferred POMC compound binds to and / or activates an MC2-R and / or an MC5-R, and does not bind to, binds with very low affinity to (i.e., whereby the receptor is not activated or is not activated to a degree to provide a significant biological activity), and / or does not substantially activate, any other melanocortin receptor under physiological conditions. In yet another embodiment, a preferred POMC compound does not bind to, binds with very low affinity to, and / or does not substantially activate an MC4-R under physiological conditions. In another embodiment, wherein an increase in body weight and / or mass is the goal, although the POMC compound preferably binds to an MC2-R and / or MC5-R with a higher affinity (or avidity) than to an MC4-R in order to minimize central nervous system effects, the POMC compound (e.g., an antagonist), preferably inhibits the activation of an MC2-R and / or MC5-R. In addition to POMC antagonist compounds as described above, an antibody that binds to and blocks the receptor and / or a soluble MC2-R or MC5-R that competes with the endogenous receptor can be administered.

[0146] Preferably, a POMC compound that binds to an MC2-R or an MC5-R binds to such receptors with at least a 10 fold greater affinity or avidity as compared to binding to an MC4-R, and more preferably, at least a 100 fold greater affinity or avidity, and more preferably, at least a 1000 fold greater affinity or avidity and even more preferably, at least a 10,000 fold greater affinity or avidity as compared to binding of the same compound to an MC4-R. A POMC compound useful for body weight loss or decrease in weight gain (including prevention of weight gain, or maintenance of weight) preferably induces or increases the activity of an MC2-R and / or an MC5-R at least about 10 fold more as compared to the activity of an MC4-R contacted with the same compound, and preferably, at least about 100 fold more, and more preferably, at least about 1000 fold more, and even more preferably, at least about 10,000 fold more as compared to the activity of an MC4-R contacted with the same compound.

[0147] In a preferred embodiment, the POMC compound can include any peptide that has an amino acid sequence which includes the amino acid sequence represented herein by SEQ ID NO:1 (EHFRW), or a homologue or mimetic thereof, which, when administered in an effective manner to a patient, has the ability to measurably regulate body weight in such patient. Peptides which have an amino acid sequence that includes SEQ ID NO:1 preferably also have one or more of the identifying characteristics of a POMC compound as described above.

[0148] In another embodiment, a preferred POMC compound includes, but is not limited to, a melanocortin and / or a lipocortin, fragments of such peptides, homologues of such peptides, mimetics (peptide or non-peptide) of such peptides, fusion proteins comprising such peptides, and any pharmaceutical salts of such peptides. Melanocortins include, but are not limited to: adrenocorticotrophin (ACTH), α-melanocyte stimulating hormone (α-MSH), β-melanocyte stimulating hormone (β-MSH) and γ-melanocyte stimulating hormone (γ-MSH); and β-endorphin. Preferred melanocortins include melanocyte stimulating hormones (MSH), fragments of such peptides, homologues of such peptides, mimetics (peptide or non-peptide) of such peptides, fusion proteins comprising such peptides, and any pharmaceutical salts of such peptides. Particularly preferred MSH peptides include α-MSH, β-MSH and γ-MSH, fragments of such peptides, homologues of such peptides, mimetics (peptide or non-peptide) of such peptides, fusion proteins comprising such peptides, and any pharmaceutical salts of such peptides.

[0149] The nucleic acid and amino acid sequences for the naturally occurring POMC peptides in a large variety of animals (i.e., human, mouse, rat, rabbit, bovine, ovine, macaque, amphibian, etc.) are known in the art. Such sequences can be found, for example, in a protein or nucleic acid database such as GenBank. GenBank accession numbers for such POMC peptide (i.e., amino acid) sequences include, but are not limited to: Accession Nos. NP—000930 or CAA24754 (Homo sapiens); Accession No. PO6297 (rabbit); Accession No. P01194 (rat); Accession No. P01193 (mouse); Accession No. P01191 (sheep); Accession No. P01190 (bovine); and Accession No. CTMKP (pig-tailed macaque). GenBank accession numbers for such POMC nucleic acid sequences include, but are not limited to: Accession No. NM—000939 (Homo sapiens); Accession No. AH005319 (mouse); Accession Nos. J00016, J00019, J00021 (bovine); Accession No. S73519 (swine); S57982 (ovine); and Accession No. AH002232 (rat).

Problems solved by technology

Preferably, administration of the compound is insufficient to cause a statistically significant change in the appetite of the animal as compared to before administration of the compound.

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