Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-02-08
2002-01-01
Celsa, Bennett (Department: 1627)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S012200, C514S013800, C530S324000, C530S325000, C530S326000
Reexamination Certificate
active
06335319
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the treatment of obesity in animals. In particular, the invention relates to the treatment of obesity in humans, although it is to be understood that the present invention also extends to the treatment of obesity in non-human mammals, for example, for the improvement of meat qualities in farm animals used in food production.
BACKGROUND OF THE INVENTION.
The critical role of human growth hormone (hGH) in postnatal growth in humans is well recognised. Less obvious is the impact of this hormone on the regulation of lipid and carbohydrate metabolism, due to lack of detailed molecular studies.
It is well documented that the predominant form of hGH is a globular protein with a molecular weight of 22,000 daltons (22-KD) and consists of 191 amino acid residues in a single-chain, folded by 2 disulphide bonds with a small loop at the carboxyl terminus between residues 182 and 189. Recent crystallographic studies also show that the hGH molecule contains four anti-parallel &agr;-helices which are arranged in a left-twisted, tightly-packed helical bundle
1
. The concept that there are discrete functional domains within the hGH molecule responsible for specific metabolic actions of the hormone is generally accepted. The amino-terminus has, been identified as the functional domain responsible for the insulin-like actions of the hGH molecule
2,3
.
Recombinant DNA technology opens the way to the large-scale commercial production of human growth hormone, and the recombinant hGH appears to have equivalent biological efficacies and pharmacokinetic properties
4,5
. Current supply of this multiple-functional hormone no longer restricts the types and numbers of experimental therapies in humans and animals. The use of hGH for treatment of short stature in children and adults is well-established
6
. Therapeutic effects of hGH in female infertility have also been reported
7,8
. Treatment of human obesity with hGH has been advocated because of its remarkable effects on body composition with lipid metabolism. However, the clinical applications of the intact hormone encounter a variety of problems. Evidence suggests that this multiple-functional hormone often simultaneously exerts in vivo, by various bioactive domains within the molecules, some adverse effects
10
.
Regulation of lipid metabolism by GH was first described in 1959 by Raben & Hollenberg
11
. The acute increase of plasma free fatty acids after GH administration was the major evidence for this metabolic function of the hormone. The regulatory role of the hormone in lipid metabolism was subsequently supported by the body composition studies of GH-deficient and GH-treated humans
12,13
and pigs
14,15
. The findings of Gertner suggest that hGH is linked to adipose tissue distribution through a series of interactions known as the“GH-fat cycle”
16
. However, the molecular events transpiring to these biochemical and physiological changes remained largely unknown. The metabolic effects of GH on adipose and other tissues in vivo are variable and complex, apparently consisting of at least two components, an early insulin-like effect followed by a later more profound anti-insulin effect
17
. The results of the latter effect may include both a stimulation of lipolysis and an inhibition of lipogenesis. The anti-lipogenic effect of hGH has been substantiated with the demonstrations of the decrease of the expression of glucose transporter GLUT 4 in adipocytes
18
, the inhibition of the activity of acetyl-CoA carboxylase in adipose tissues
19,20
and the reduction of glucose incorporation into lipid in both isolated cells and tissues
21,22
.
In view of the multiple-functional effects of intact hGH and the problems encountered in clinical applications of the intact hormone, work leading to the present invention has been directed to investigating whether hGH derivatives could be synthesised that retain the desired bioactivities and lack the unwanted side effects. In this work, structure-function studies of hGH have been carried out to elucidate the molecular mechanism of the metabolic actions of this multiple-functional hormone.
SUMMARY OF THE INVENTION
The present invention concerns a method for treating obesity comprising administering an effective amount of a peptide wherein the amino acid sequence of the peptide comprises the carboxyl-terminal sequence of a growth hormone. The treatment may be administered to any animal, including humans. The peptide may comprise the carboxyl-terminal sequence of human growth hormone or the growth hormone of a non-human mammalian species.
In one embodiment of the invention, the peptide comprises the carboxyl-terminal sequence of human growth hormone containing amino acid residues 177-191. In other embodiments of the invention, the peptide comprises the carboxyl-terminal sequence of the growth hormone of a non-human mammalian species corresponding to amino acid residue 177-191 of human growth hormone.
In another aspect, the present invention also concerns a pharmaceutical composition for use in the treatment of obesity comprising an effective amount of a peptide wherein the amino acid sequence of the carboxyl-terminal sequence of a growth hormone, and one or more pharmaceutically acceptable carriers and/or diluents. The peptide may comprise the carboxyl-terminal sequence of human growth hormone or the growth hormone of a non-human mammalian species.
In one embodiment of this aspect of the invention, the peptide comprises the carboxyl-terminal sequence of human growth hormone containing amino acid residues 177-191. In other embodiments of this aspect of the invention, the peptide comprises the carboxyl-terminal sequence of the growth hormone of a non-human mammalian species corresponding to amino acid residues 177-191 of human growth hormone.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The structure-function studies of hGH with synthetic hormonal fragments have revealed that the carboxyl terminus of the hGH molecule appears to be the functional domain of the hormone for the regulation of lipid metabolism
20,23,24,25
and it has now been shown that a synthetic peptide having a sequence based in the carboxyl terminal region reduces body weight gain and adipose tissue mass in a laboratory obese animal model.
According to one aspect of the present invention, there is provided a method for the treatment of obesity in an animal, which comprises administering to the animal an effective amount of a peptide wherein the amino acid sequence of the peptide comprises the carboxyl-terminal sequence of a growth hormone, and wherein the peptide is not the intact, full length growth hormone.
Preferably, the animal is a human although the invention also extends to the treatment of non-human mammals. Preferably also, the peptide comprises the carboxyl-terminal sequence of human growth hormone containing amino acid residues 177-191 (SEQ ID NO: 1), hereinafter referred to as hGH 177-191. Alternatively, the peptide may comprise the carboxyl-terminal sequence of the growth hormone of other non-human mammalian species, such as bovine, porcine, ovine, equine, feline or canine growth hormone corresponding to the hGH 177-191 peptide.
As used throughout this specification, the term“obesity” is used to include both excess body weight and excess adipose tissue mass in the animal, and correspondingly the references to treatment of obesity include both reduction of body weight gain and reduction of adipose tissue mass of the obese animal.
As described above, the carboxyl-terminal sequence of a growth hormone include a bioactive lipid methabolic domain effective to reduce body weight gain and adipose tissue mass in an obese animal. Thus, the peptide comprising the carboxyl-terminal sequence of a growth hormone in accordance with the present invention has in vivo lipid metabolic active, particular in vivo antilipogenesis and lipolytic activity.
The expected outcome of any treatment of obesity is the reduction of body weight, body adipose tissue mass in particular. The reduction of body adipose tissue mass is dir
Jiang Woei-Jia
Natera Siria Helen Anna
Ng Frank Man-Woon
Celsa Bennett
Metabolic Pharmaceuticals, Inc.
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