Title of Invention

"HYBRID POLYPEPTIDES WITH SELECTABLE PROPERTIES HAVING ENHANCED ACTIVITIES"

Abstract

The present invention relates to novel hybrid polypeptides comprising at least two covalently-linked active hormonal peptides useful as agents for the treatment and prevention of metabolic diseases and disorders which can be alleviated by control plasma glucose levels, insulin levels, and/or insulin secretion, such as diabetes and diabetes-related conditions. The two hormone peptides are selected independently from at least two of amylin, adrenomedullin (ADM), calcitonin (CT), calcitonin gene related peptide (CGRP), intermedin, cholecystokinin ("CCK"), leptin, peptide YY (PYY), glucagon-like peptide-1 (GLP-1), glucagon-like peptide 2 (GLP-2), oxyntomodulin (OXM), and exendin-4. Such conditions and disorders include, but are not limited to, hypertension, dyslipidemia, cardiovascular disease, eating disorders, insulin-resistance, obesity, and diabetes mellitus of any kind, including type 1, type 2, and gestational diabetes.

Full Text

HYBRID POLYPEPTIDES WITH SELECTABLE PROPERTIES BELATED APPLICATIONS The present applicatio claims filed February 11, 2004, which The present invention relates polypeptides with selectable priority to U.S. Provisional Application No. 60/543,407, is hereby incorporated by reference in its entirty. FIELD OF THE INVENTION to peptide chemistry, and more particularly to hybrid pe rties. BACKGROUND OF THE INVENTION Central to many metabolic dis« ases and disorders is the regulations of insulin levels and blood glucose levels. Insuli n termed as incretins, which are glucagon-like peptide-1 ("GLP ecretion is modulated in part by secretagogue hormones, reduced by enteroendocrine cells. The incretin hormone, 1") is a peptide hormone secreted by intestinal cells that has been shown in multiple stx dies to produce an enhancing effect on insulin secretion. GLP-1 is processed from prog ucagon in the gut and enhances nutrient-induced insulin release (Krcymann B., et ai, Lancet, 2:1300-1303 (1987)). Various truncated forms of GLP-1, are known to stimul formation [see, e.g., Mojsov, relationship between various /> human, insulinotropic respons amide, and GLP-1 (7-37) acid Diabetohgia, 36:741-744 (1 te insulin secretion (insulinotropic action) and cAMP S., Int. J. Pep. Pro. Res., 40:333-343 (1992)]. A vitro laboratory experiments and mammalian, especially s to exogenous administration of GLP-1, GLP-1(7-36) has been established (see, e.g., Nauck, M. A., et al., 93); Gutniak, M., et al, New Eng. J. of Med., 326(20):1316-1322 (1992); Nauck, M. A., et al., J. Clin. Invest., 91:301-307 (1993); and Thorens, B.,etal., Diabetes, 4: 1219-1225(1993)). i GLP-1(7-36) amide exerts a ironounced antidiabetogenic effect in insulin-dependent diabetics by stimulating insulin sensitivity and by enhancing glucose-induced insulin release at physiological concen rations (Gutniak M., et al, New Eng. J. Med, 326:1316-1322 (1992)). When administered to non-insulin dependent diabetics, GLP-1(7-36) amide stimulates insulin release, lowers glucagon secretion, inhibits gastric emptying and enhances glucose utilization (Nauck, 1993; Gutniak, 1992; Nauck, 1993). However, the use of GLP-1 type moleculesfor prolonged therapy of diabetes has been complicated because the serum half-life of such peptides is quite short. More particularly, GLP-1 is a J30-amino acid peptide derived from proglucagon, a 160-amino acid prohormone. Actions of different prohormone convertases in the pancreas and intestine result in the production of glucagons and other ill-defined peptides, whereas cleavage of proglucagon results in the production of GLP-1 and GLP-2 as well as two other peptides. The amino acid sequence of GLP-1 is 100% homologous in all mammals studied so far, implying a critical physiological role. GLP-1 (7-37) acid is C-terminally GLP-1 (7-36) NH2. The biological effects and metabolic turnover of the free acid GL^-1 (7-37) OH, and the amide, GLP-1 (7-36) NH2, are indistinguishable. By convention, the numbering of the amino acids is based on the processed GLP-1 (1-37) OH f-om proglucagon. The biologically active GLP-1 is the result of further processing: GlLP-1 (7-36) NH2. Thus the first amino acid of GLP-1 (7- 37)OHorGLP-l(7-36)NH2is 7His. In the gastrointestinal tract, GLP-1 is produced by L-cells of intestinal, colonic and rectal mucosa, in response to stimu ation by intraluminal glucose. The plasma half-life of active GLP-1 is I peptidase (DPP) IV (CD26) [which cleaves the N-terminal His-Ala dipeptide, thus producing metabolites, GLP-1 j (9-37) OH or GLP-1 (9-36) NH2 which are variously described as inactive, weak agonist or antagonists of GLP-1 receptor. GLP-1 receptor (GLP-1 R) is a G protein coipled receptor of 463 amino acid and is localized in pancreatic beta cells, in the lungs and to a lesser extent in the brain, adipose tissue and kidneys. The stimulation of G,P-1R by GLP-1 (7-37) OH or GLP-1 (7-36)NH2 results in adenylate cyclase activation, cAMP synthesis, membrane depolarization, rise in intracellular calcium and increase in glucose-induced insulin secretion (Holz et al., 1995). GLP-1 is a potent insulin secretagogue that is secreted from the intestinal mucosa in response to food intake. The profound incretin effect of GLP-1 is underscored by the fact that GLP-1 R knockout mice an: glucose-intolerant. The incretin response of i.v. infused GLP-1 is preserved in diabetic subjects, though the incretin response to oral glucose in these patients is compromised. GLP-1 administration by infusion or sc injections controls fasting glucose levels in diabetic patients, and maintains the glucose threshold for insulin secretion (Gutniak e't al, 1992; Nauck et al, 1986; Nauck et al., 1993). GLP-1 has shown tremendous potential as a therapeutic agent capable of augmenting insulin secretion in a physiological jnanner, while avoiding hypoglycemia associated with i sulfonylurea drugs. Other important effects of GLp-1 on glucose homeostasis are suppression of glucagon secretion and inhibition of gastric motility. GLP-1 inhibitory actions on pancreatic alpha cell secretion of glucagon leads to decreases in hepatic glucose production via reduction in gluconeogenesis and glycogenolysis. This antiglucagon effect of GLP-1 is preserved in diabetic patients. The so-called ileal brake effect of GLP-1, in which gastric motility and gastric secretion are inhibited, is effected via vagal efferent receptors or by direct action on intestinal smooth muscle. Reduction of {gastric acid secretion by GLP-1 contributes to a lag phase in nutrient availability, thus obviating the need for rapid insulin response. In summary, the gastrointestinal effects of G,P-1 contribute significantly to delayed glucose and fatty acid absorption and modulate insulin secretion and glucose homeostasis. GLP-1 has also been shown to induce beta cell specific genes, such as GLUT-1 transporter, insulin (via the interaction of PDX-1 with insulin gene promoter), and hexokinase-1. Thus GLP-1 i ould potentially reverse glucose intolerance normally associated with aging, as demonstrated by rodent experiments. In addition, GLP-1 may contribute to beta cell neogenes s and increase beta cell mass, in addition to restoring beta cell function during states of beta cell insufficiency.I Central effects of GLP-1 include increases in satiety coupled with decreases in food intake, effected via the action j of hypothalamic GLP-1 R. A 48 hour continuous SC infusion of GLP-1 in type II diabetic subjects, decreased hunger and food intake and increased satiety. These anorec|tic effects were absent in GLP-1 R knock out mice. Exendins are another family c peptides implicated in insulin secretion. Exendins are found in the saliva of the Gila-inonster, a lizard endogenous to Arizona, and the Mexican Beaded Lizard. Exendin-3 is p •esent in the saliva of Heloderma horridum, and exendin-4 is present in the saliva of Heloderma suspectum (Eng, J., et al, J. Biol. Chem., 265:20259-62, 1990; Eng., J., I/ al., J. Biol. Chem., 267:7402-05 (1992)). The exendins have some sequence similarit y with the highest homology, to several members of the glucagon-like peptide family, 53 %, being to GLP-1 (Goke, et al., J. Biol. Chem., 268:19650-55(1993)). Exendin-4 binds the GLP-1 receptors on insulin-secreting TCI cells, at dispersed acinar cells from guinea pig pancreas, and at parietal cells from stomach; the peptide also stimulates somatostatin release and inhibits gastrin release in isolated stomachs (Goke, et al, J. Biol. Chem., 268:1965055 (1993); Schepp, et al, Eur. J. Pharmacol, 69:183-91 (1994); Eissele, et al, Life Sci., 55:629-34 (1994)). Exendin-3 and exendin-4 were found to bind the GLP-1 receptors on, to stimulating cAMP production in, and amylase release from, pancreatic acinar cells (Malhotra, R., et al, Relulatory Peptides, 41:149-56 (1992);Raufman, et al, J. Biol Chem. 267:21432-37 (1992); Singh, et al, Regul Pept., 53:47- 59 (1994)). The use of the injiulinotropic activities of exendin-3 and exendin-4 for the treatment of diabetes mellitus and the prevention of hyperglycemia has been proposed (Eng, U.S. Pat. No. 5,424,286). Truncated exendin peptides sijch as exendin[9-39], a carboxyamidated molecule, and fragments 3-39 through 9-39 h* ve been reported to be potent and selective antagonists of GLP-1 (Goke, et al, J. Biol. Chem., 268:19650-55 (1993); Raufman, J. P., et al, J. Biol Chem., 266:2897-902 (1991); Schepp, W., et al, Eur. J. Pharm., 269:183-91 (1994); Montrose-Rafizadeh, et al., Diabetes, 45(Suppl. 2):152A (1996)). Exendin[9-39] blocks endogenous GLP-1 in vivo, resulting in reduced insulin secretion (Wang, et al, J. Clin. Invest., 95:417-21 (1995); D'Alessio, et al, J. Clin. Invest., 97:133-38 (1996)). The receptor apparently responsible for the insulinotropic effect of GLP-1 has been cloned from rat pancreatic islet cells (Thorens, B., Proc. Natl. Acad. Sci. USA 89:8641-8645 (1992)). Exendins and exendin[9-39] bind to the cloned GLP-1 receptor (rat pancreatic - cell GLP-1 receptor: Fehmann HC, et al., Peptides, 15 (3): 453-6 (1994); human GLP-1 receptor: Thorens B, et al., Diabetes, 42 (11): 1678-82 (1993)). In cells transfected with the cloned GLP-1 receptor, GLP-1. Id. More particularly, exendin-4 is a 39 amino acid C-terminal amidated peptide found in the saliva of the Gila Monster (Heloderma horridum), with a 53% amino acid sequence homology to the GLP-1 peplide sequence. See, e.g., Eng, J., et al. "Isolation and Characterization of Exendin-4, and Exendin-3 Analogue from Heloderma suspectum Venom," J. Bio. Chem., 267: 1, p. 7402-7405 (1992), Young, A. A., et al., "Glucose- Lowering and Insulin-Sensitizjing Actions of Exendin-4," Diabetes, Vol. 48, p. 1026-1034, May, 1999. In terms ofjits activity, exendin-4 is a highly specific agonist for the GLP-1 receptor, and, like GLI '-1, is able to stimulate insulin secretion. Therefore, like GLP-1, exendin-4 is regarded as an insulinotropic peptide. However, unlike GLP-1, exendin-4 has a relatively long half-life in humans, because of its resistance to the dipeptidyl peptidase IV which rapidly degrades the GLP-1 sequence in vivo. Furthermore, it has b^en shown that, as compared to GLP-1, exendin-4 has a stronger capability to stimulate insulin secretion, and that a lower concentration of exendin-4 may be used to obtain such stimulating activity. See, e.g., U.S. Pat. No, 5,424,286, herein incorporated by reference. Therefore exendin-4 peptides or derivatives thereof (for examples of suet derivatives, see, e.g., U.S. Pat. No. 6,528,486, herein incorporated by reference, and have a greater potential utility its corresponding international application WO 01/04156) or the treatment of conditions involving the dysregulation of insulin levels (e.g., conditior s such as diabetes) than either insulin or GLP-1. I Another family of peptide hornkones implicated in metabolic diseases and disorders is the amylin family of peptide hormbnes, including amylin, calcitonin, calcitonin gene related peptide, adrenomedullin, and intermedin (also known as "AFP-6"). Amylin is a 37- amino acid protein hormone. It was isolated, purified and chemically characterized as the major component of amyloic deposits in the islets of pancreases of human Type 2 diabetics (Cooper et al., Proc. molecule has two post-transla Natl. Acad Sci., USA, 84:8628-8632 (1987)). The amylin ional modifications: the C-terminus is amidated, and the cysteines in positions 2 and 7 ire cross-linked to form an N-terminal loop. The sequence of the open reading frame of the human amylin gene shows the presence of the Lys-Arg dibasic amino acid proteolytic cleavage signal, prior to the N-terrninal codon for Lys, and the Gly prior to the Lys-Argproteolytic signal at the CLAIMS-terminal position, a typical sequence for amidation by protein amidating enzyme, PAM (Cooper et al., Biochem. Biophys. Acta, 1014: 247-258(1989)). Amylin is believed to regulate gastric emptying, and suppress glucagon secretion and food intake, thus regulating th to complement the actions of : rate of glucose appearance in the circulation. It appears ns ulin, which regulates the rate of glucose disappearance from the circulation and its upake by peripheral tissues. These actions are supported by experimental findings in rodents and humans, which indicate that amylin complements the effects of insulin in pos prandial glucose control by at least three independent mechanisms, all of which affect the rate of glucose appearance. First, amylin suppresses postprandial glucagon secretion. Compared to healthy adults, patients with type 1 diabetes have no circulating amylin and patients with type 2 diabetes have diminished postprandial amylin concenaations. Furthermore, infusion of an amylin specific monoclonal antibody, which bound circulating amylin, again resulted in greatly elevated glucagon concentrations relative to controls. Both of these results point to a physiological role of endogenous amylin in the regulation of postprandial glucagon secretion. Second, amylin slows gastrointestinal motility and gastric emptying. Finally, intrahypothalamic injections ol rat amylin were shown to reduce feeding in rats and alter neurotransmitter metabolism ii the hypothalamus. In certain studies, food intake was significantly reduced for up tc eight hours following the intrahypothalamic injection of rat amylin and rat CORP. In human trials, an amylin analog, pramlintide, has been shown to reduce weight or weight gain. Amylin may be beneficial in treating metabolic conditions such as diabetes and obesity. Amylin may also be used to treat pain, bone disorders, gastritis, to modulate lipids, in particular triglycerides, or to affect body composition such as the preferential loss of fat and sparing of lean tissue. The hormone calcitonin (CT) was named for its secretion in response to induced hypercalcemia and its rapid hypocalcemic effect. It is produced in and secreted from neuroendocrine cells in the thyroid that have since been termed C cells. The best-studied action of CT(l-32) is its effect on the osteoclast. In vitro effects of CT include the rapid loss of ruffled borders and decreased release of lysosomal enzymes. Ultimately, the inhibition of osteoclast functions by CT results in a decrease in bone resorption.1 However, neither a chronic reduction of serum CT in the case of thyroidectomy nor the| increased serum CT found in medullary thyroid cancer appears to be associated with changes in serum calcium or tone mass. It is thus most likely that a major function of CT(l-32) is to combat acute Ijiypercalcemia in emergency situations and/or protect thei skeleton during periods of "calcium stress" such as growth, pregnancy, and lactation (Reviewed in Becker, JCEM, 89(4): 1512-1525 (2004) and Sexton, Current Medicinal] Chemistry 6: 1067-1093 (1999)). Consistent with this is recent data from the calcitonin1 gene knockout mouse, which removes both the calcitonin and the CGRP-I peptides, that revealed that the mouse had increased calcemic response normal levels of basal calcium-related values, but an (Kurihara H, et al, Hypertens Res. 2003 Feb; 26 Suppl:S 105-8). CT has an effect on plasma calcium levels and inhibits osteoclast function and is widely used for the treatment of osteoporosis. Therapeutically, salmon CT (sCT) appears to; increase bone density and dectease fracture rates with minimal adverse effects. CT has also been successfully used over the past 25 years as a therapy for Paget's disease of bone, which is a chronic skeletal disorder that may result in enlarged or deformed bones in one or more regions of the skeleton. CT is also widely used for its analgesic effect onj bone pain experienced during osteoporosis, although the mechanism for this effect is not, clearly understood. j I Calcitonin gene related peptidjs (CGRP) is a neuropeptide whose receptors are widely, distributed in the body, including the nervous system and the cardiovascular system. This peptide seems to modulate sensory neurotransmission and is one of the most potent endogenous vasodilatory peptide discovered to date. Reported biological effects for CGRP include: modulation of substance P in inflammation, nicotinic receptor activity at the neuromuscular junction, stimulation of pancreatic enzyme secretion, a reduction of gastric acid secretion, peripheral vasodilation, cardiac acceleration, neuro-modulation, regulation of calcium metabol sm, osteogenic stimulation, insulin secretion, an increase in body temperature and a decrease in food intake. (Wimalawansa, Amylin, calcitonin gene-related peptide, calcitonii and ADM: a peptide superfamily. Crit Rev Neurobiol. I 1997; 11(2-3): 167-239). An important role of CGRP is to control blood flow to various i organs by its potent vasodilatory actions, as evidenced by a decrease of mean arterial I pressure following intravenous! administration of a-CGRP. The vasodilatory actions are also supported by recent analysis of homozygous knockout CGRP mice, which demonstrated elevated peripheral vascular resistance and high blood pressure caused by increased peripheral sympathetic activity (Kurihara H, et ai, Targeted disruption of ADM and aCGRP genes reveajls their distinct biological roles. Hypertens Res. 2003 Feb; 26 Suppl:S 105-8). Thus, CGRJP appears to elicit vasodilatory effects, hypotensive effects and an increase in heart rate among other actions. vascular disease such as hypertension, and pulmonary preterm labor is also potential 1) Prolonged infusion of CGRP Into patients with congestive cardiac failure has shown a sustained beneficial effect on hsmodynamic functions without adverse effects, suggesting a use in heart failure. Other : ndications of CGRP use include renal failure, acute and chronic coronary artery ischemia, treatment of cardiac arrhythmia, other peripheral Raynaud's phenomenon, subarachnoid hemorrhage, hypertension. Preeclamptic toxemia of pregnancy and treatable. (Wimalawansa, 1997). Recent therapeutic uses include the use of CGRP antagonists for the treatment of migraine headaches. Adrenomedullin (ADM) is a most ubiquitously expressed with many more tissues containing the peptide than nDt. A published review of ADM, (Hinson, J.P. et al, Endocrine Reviews (2000) 2 (2): 138-167) details its effects on the cardiovascular system, cellular growth, the central nervous system and the endocrine system, with a range of biological actions including vasodilation, cell growth, regulation of hormone secretion, and natriuresis. Studies in rat, cat, sheep, and man confirm that intravenous infusion of ADM results in pc|tent and sustained hypotension, and is comparable to that i of CGRP. However, the hypptensive effect of ADM on mean arterial pressure in the anesthetized rat is not inhibited by the CGRP antagonist CGRPs-37 suggesting that this j effect is not mediated via CGJIP receptors. Acute or chronic administration of human ADM in rats, anesthetized, conscious or hypertensive, results in a significant decrease in total peripheral resistance accompanied by a fall in blood pressure, with a concomitant rise in heart rate, cardiac output and stroke volume. ADM has also been proposed as an important factor in embryogenesis and differentiation and as an apoptosis survival fsctor for rat endothelial cells. This is supported by recent mouse ADM knockout studies, in which mice homozygous for loss of the ADM gene demonstrated defective vascular formation during embryogenesis and thus died mid- gestation. It was reported th^t ADM +/- heterozygous mice had high blood pressure along with susceptibility to tissjue injury (Kurihara H, et a/., Hypertens Res. 2003 Feb; 26 Suppl:S 105-8). ADM affects such endocrine organs as the pituitary, the adrenal gland, reproductive organs and the pancreas. The jeptide appears to have a role in inhibiting ACTH release from the pituitary. In the adrenal gland, it appears to affect the secretory activity of the adrenal cortex in both rat and human and it increases adrenal blood flow, acting as a vasodilator in the adrenal vascular bed in intact rats. ADM has been shown to be present I throughout the female reproductive tract and plasma levels are elevated in normal pregnancy. Studies in a ratj model of preeclampsia show that ADM can reverse hypertension and decrease pup mortality when given to rats during late gestation. Because it did not have a similar effect in animals in early gestation or non-pregnant rats [ in the preeclampsia model, this suggests that ADM may play an important regulatory role in the utero-placental cardiovascular system. In the pancreas, ADM most likely plays an inhibitory role since it attenuated and delayed insulin response to an oral glucose' challenge, resulting in initial j elevated glucose levels. ADM can also affect renal function. A bolus administered peripherally can significantly lower mean arterial pressure and raise renal blood flow, glomerular filtration rate and urine flow. In some cases, there is also an increase in Na+ excretion.i ADM also has other peripheral effects on bone and on the lung. For bone, studies have supported a role beyond the cardiovascular system and fluid homeostasis and have demonstrated that ADM acts on fetal and adult rodent osteoblasts to increase cell growth comparable to those of knowi osteoblast growth factors such as transforming growth factor-p. This is important clinically as one of the major challenges in osteoporosis research is to develop a therapy that increases bone mass via osteoblastic stimulation. Ini the lung, ADM not only] causes pulmonary vasodilation, but also inhibitsby histamine or acetylcholine. Recent studies using bronchoconstriction induced aerosolized ADM to treat pulmonary hypertension in a rat model indicate that inhalation treatment of this condition is effective, as evidenced by the fact that mean pulmonary arterial pressure and total pulmonary resistance were markedly lower in rats treated with ADM than in those given saline. This result was achieved without an alteration in systemic arterial pressure or heart rate (Nagaya N et al, Am J Physiol Heart Ore Physiol. 2003;285:H2125-31).| I In healthy volunteers, i.v. infvsion of ADM has been shown to reduce arterial pressure and to stimulate heart rate, cardiac output, plasma levels of cAMP, prolactin, norepinephrine and rennin. In these patients, there was little or no increase in urine volume or sodium excretion observed. In patients with heart failure or chronic renal failure, i.v. ADM had similar effects to those seen in normal subjects, and also induced diuresis and natriuresis, depending on the dose administered (Nicholls, MG et al. Peptides. 2001; 22:1745-1752] Experimental ADM treatment has also been shown to be beneficial in arterial and pulmonary hypertension, septic shock and ischemia/reperfusion injury (Beltowski J., Pol J Pharmacol. 2004;56:5-27). Other indications for ADM treatment include: peripheral vascular disease, subarachnoid hemorrhage, hypertension, preeclamptic toxemia of pregnimcy and preterm labor, and osteoporosis. Expression of AFP-6 (i.e., intjjrmedin) is primarily in the pituitary and gastrointestinal tract. A specific receptor for AFP-6 has not been reported; however, binding studies indicate that AFP-6 binds to all the known receptors of the Amylin Family. AFP-6 has been shown to increase cAMP production in SK-N-MC and L6 cells expressing endogenous CGRP receptors and competes with labeled CGRP for binding to its receptors in these cells. In published in vivo studies, AFP-6 administration led to blood pressure reduction in both noimal and spontaneously hypertensive rats, most likely via interactions with the CRLR/RAMP receptors. In vivo administration in mice led to a suppression of gastric emptying and food intake. (Roh et al. J Biol Chem. 2004 Feb 20;279(8):7264-74.) It has been reported that the biological actions of amylin family peptide hormones are generally mediated via binding to two closely related type II G protein-coupled receptors (GPCRs), the calcitonin receptor (CTR) and the calcitonin receptor like receptor (CRLR). Cloning and functional studies different combinations of CTR have shown that CGRP, ADM, and amylin interact with or the CRLR and the receptor activity modifying protein (RAMP). Many cells express i multiple RAMPs. It is believed that co-expression of RAMPs and either the CTR or CRLR is required to generate functional receptors for calcitonin, CGRP, ADM, and amylin. The RAMP family comprises three members (RAMP1, -2, and -3), which sliare less then 30% sequence identity, but have a common topological organization. Co-ejxpression of CRLR and RAMP1 leads to the formation of a receptor for CGRP. Co-exp-ession of CRLR and RAMP2 leads to the formation of a receptor for ADM. Co-expression of CRLR and RAMP3 leads to the formation of a receptor for ADM and CORK Co-expression of hCTR2 and RAMP1 leads to the formation of a receptor for amylin and CGRP. Co-expression of hCTR2 and RAMP3 leads to the formation of a rece rtor for amylin. Yet another peptide hormone fiimily implicated in metabolic diseases and disorders is the leptin family. The mature fonn of circulating leptin is a 146-amino acid protein that is normally excluded from the CNS by the blood-brain barrier (BBB) and the blood-CSF barrier. See, e.g., Weigle et al. 1995. J Clin Invest 96 : 2065-2070. Leptin is the afferent signal in a negative feedback regulating food intake and body weight. The leptin receptor is a member of the cytokine receptor family. Leptin's anorexigenic effect is dependent on binding to homotiimer of the Ob-Rb isoform of this receptor which encodes a long intra-cytoplasmic dopiain that includes several motifs for protein-prtein interaction. Ob-Rb is highly region is an important site ofexpressed in the hypothalamus suggesting that this brain leptin action. Mutation of the mouse ob gene has been demonstrated to result in a syn impaired thyroid and reproduc obese mice (see e.g., Ingalis, ive functions in both male and female homozygous ob/ob ',t al., 1950. J Hered4l : 317-318. Therapeutic uses for leptin or leptin receptor inclide (i) diabetes (see, e.g., PCT Patent Applications WO 98/55139, WO 98/12224, and WO 97/02004); (ii) hematopoiesis (see, e.g., PCT Patent Applications WO 97/27286 and WO 98/18486); (iii) infertility (see, e.g., PCT Patent Applications WO 97/15322 and WO 98/36763); and (iv) tumor suppression (see, e.g., PCT Patent Applications WO 98/48f!31), each of which are incorporated herein by reference in their entirety. and mapping to the db locus Several transcripts of the OE The leptin receptor (OB-R) gelne has been cloned (GenBank Accession No. AF098792) (see, e.g., Tartaglia, et al., 1995. Cell 83: 1263-1271). -R, resulting from alternative splicing, have also been identified. Defects in OB-R produce a syndrome in the mutant diabetic ob/ob mouse that is phenotypically identical to the ob/ob mouse (see, e.g., Ghilardi, et a/., 1996. Proc. Natl. Acad. Sci. USA 93: 6231-623f ). In contrast to ob/ob mice, however, administration of recombinant leptin to C57BLKS/J-m ob/ob mice does not result in reduced food intake and body weight (see, e.g., Roberts and Greengerg, 1996. Nutrition Rev. 54: 41-49). Most leptin-related studies able to report weight loss activity from administration of recombinant leptin, leptin fragments and/or leptin receptor variant have administered said constructs directly into the ventricles of the brain. See e.g., Weigle, et al, 1995. J Clin Invested : 2065-2070; Barash,^0/., 1996. Endocrinology 137: 3144-3147. Other studies have shown sigiificant weight loss activity due to administered of leptin peptides through intraperitoneally (i.p.) administration to test subjects. See, Grasso et al., 1997. Endocrinology 138: 141 • -1418. Further, leptin fragments, and most particularly an 18 amino acid fragment composing residues taken from full length human leptin, have been reported to function in w sight loss, but only upon direct administration through an implanted cannula to the lateral brain ventricle of rats. See, e.g., PCT Paten Applications WO 97/46585, which is incorporated herein by reference in its entirety. Another peptide hormone cholecystokinin (CCK). CCK implicated in metabolic diseases and disorders is was reportedly identified in 1928 from preparations of intestinal extracts by its abiliy to stimulate gallbladder contraction. Other biological actions of CCK have since been reported, including stimulation of pancreatic secretion, delayed gastric emptying, stimulation of intestinal motility and stimulation of insulin secretion. See Lieverse et al., Ann. N.Y. Acad. Sci. 713: 268-272 (1994). The actions of CCK, also reportedly include effects on cardiovascular function, respiratory function, neurotoxicity and seizures, cancer cell proliferation, analgesia, sleep, sexual and reproductive behaviors, memory, anxiety and dopamine-mediated behaviors. Crawley and Corwin, Peptides 15: 73J1-755 (1994). Other reported effects of CCK include stimulation of pancreatic groAJvth, stimulation of gallbladder contraction, inhibition of gastric acid secretion, pancreatic polypeptide release and a contractile component of peristalsis. Additional repotted effects of CCK include vasodilation. Walsh, "Gastrointestinal Hormones," n Physiology of the Gastrointestinal Tract (3d ed. 1994; Raven Press, New York). It has been reported that injections of combinations of glucagon, CCK and bombesin potentiated the inhibition of intake of condensed milk test meals in nondeprived rats over the inhibitions observed with individual compounds. Hinton et al. Brain Res. Bull. 17:615-619 (1986). It has also been reported that glucagon and CCK synergistically inhibit sham feeding in rats. L iSauter and Geary, Am. J. Physiol. 253:R217-225 (1987); Smith and Gibbs, Annals N.Y. Acad. Sci. 713:236-241 (1994). It has also been suggested that estradiol and CCK can haVe a synergistic effect on satiety. Dulawa et al, Peptides 15:913-918 (1994); Smith amjl Gibbs, supra. It has also been proposed that signals arising from the small intejstine in response to nutrients therein may interact synergistically with CCK to reduce food intake. Cox, Behav. Brain Res. 38:35-44 (1990). Additionally, it has been reported that CCK induces satiety in several species. For example, it has been reported that feeding depression was caused by CCK injected intraperitoneally in rats, intrairterially in pigs, intravenously in cats and pigs, into the cerebral ventricles in monkeys rats, dogs and sheep, and intravenously in obese and non- obese humans. See Lieversr et al, supra. Studies from several laboratories have reportedly confirmed the behavioral specificity of low doses of CCK on inhibition in feeding, by comparing responc ing for food to responding for nonfood reinforcers in both monkeys and rats and by stun ring that CCK elicits the sequence of behaviors normally observed after meal ingestior (i.e., the postprandial satiety sequence). Additionally, comparison of behavior after CCK to behavior after food ingestion, alone or in combination with CCK has rejwrtedly revealed behavioral similarities between CCK am food ingestion. Crawley and Corwin, supra. It has also been reported that CCK in physiological plasma concent -aliens inhibits food intake and increases satiety in both lean and obese humans. See L .everse et al, supra. CCK was characterized in 1966 as a 33-amino acid peptide. Crawley and Corwin, supra Species-specific molecular vmants of the amino acid sequence of CCK have been identified. The 33-amino acid sequence and a truncated peptide, its 8-amino acid C terminal sequence (CCK-8) chinchilla, dog and humans. have been reportedly identified in pig, rat, chicken 39-amino acid sequence was reportedly found in pig, dog and guinea pig. A 5 8-amino idd sequence was reported to have been found in cat, dog and humans. Frog and turtle both CCK and gastrin. Very reportedly show 47-amino acid sequences homologous to fresh human intestine has been reported to contain smal amounts of an even larger molecule, termed CCK-83. In the rat, a principal intermediate form has been reportedly identified, and is termed CCK-22. Walsh, "Gastrointestinal Hormones," In Physiology of he Gastrointestinal Tract (3d ed. 1994; Raven Press, New York). A non-sulfated CCK-)8 and a tetrapeptide (termed CCK-4 (CCK(30-33)) have been reported in rat brain. The C-terminal pentapeptide (termed CCK-4 (CCK(29-33)] conserves the structural homo gastrin. The C-terminal sulfa conserved across species, i ogy of CCK, and also homology with the neuropeptide ed octapeptide sequence, CCK-8, is reportedly relatively Cloning and sequence analysis of a cDNA encoding preprocholecystokinin from rat thyroid carcinoma, porcine brain, and porcine intestine reportedly revealed 345 nuclecjrtides coding for a precursor to CCK, which is 115 amino acids and contains all of the Crawley and Corwin, supra. CCK is said to be distributee cells and enteric nerves of th (also referred to as CCK-33), (CCK-5 or CCK(29-33)), and CCK receptor, CCK-8 reportedly than unsulfated CCK-8 or 1000-fold more potent than amylase secretion. Crawley CCK receptor binding was concentrations that were equimbl GCK sequences previously reported to have been isolated CCK-4 anil sail throughout the central nervous system and in endocrine upper small intestine. CCK agonists include CCK itsell CCK-8 (CCK(26-33)), non-sulfated CCK-8, pentagastrin the tetrapeptide, CCK-4 (CCK(30-33)). At the pancreatic displaced binding with a 1000-5000 greater potency , and CCK-8 has been reported to be approximately unsulfated CCK-8 or CCK-4 in stimulating pancreatic Corwin, supra. In homogenates from the cerebral cortex, to be displaced by unsulfated CCK-8 and by CCK-4 at iar, 10-fold or 100-fold greater than sulfated CCK-8. Id. Receptors for CCK have beep primary subtypes have been d receptors have been reported in sphincter and afferent vagal fibjers subtype (CCKA) has been repohed B receptor subtype (CCKB) has and reportedly does not require Nutr. 124(8Suppl.)1327S-13: Yet another family of peptide the pancreatic polypeptide 1 discovered as a contaminant rather than functional importance PP is a 36-amino acid peptide was subsequently discovered In because of the N- and C-termJnal 2514-8 (1982)). A third related reportedly identified in a variety of tissues, and two scribed: type A receptors and type B receptors. Type A peripheral tissues including pancreas, gallbladder, pyloric ers, and in discrete areas of the brain. The type A receptor to be selective for the sulfated octapeptide. The Type been identified throughout the brain and in the stomach, sulfation or all eight amino acids. See Reidelberger, J. 3S (1994); Crawley and Corwin, supra. hormones implicated in metabolic diseases and disorders is amily ("PPF"). Pancreatic polypeptide ("PP") was insulin extracts and was named by its organ of origin (Kimmel et al, Endocrinology 83: 1323-30 (1968)). ;ontaining distinctive structural motifs. A related peptide extracts of intestine and named Peptide YY ("PYY") tyrosines (Tatemoto, Proc. Natl Acad. Sci. USA 79: peptide was later found in extracts of brain and named Neuropeptide Y ("NPY") (Tatemoto, Proc. Natl. Acad. Sci. USA 79: 5485-9 (1982); Tatemoto et al, Nature 296: 6« 9-60 (1982)). These three related peptides have been reported to exert various biological effects. Effects of PP include inhibition of pancreatic secretion and relaxation of the gallbladder. Centrally administered PP procuces modest increases in feeding that may be mediated by receptors localized to the hypothalamus and brainstem (reviewed in Gehlert, Proc. Soc. Exp. Biol Med. 218: 7-22 (199^)). i Release of PYY occurs following a meal. An alternate molecular form of PYY is PYY(3-36) (Eberlein et al., Peptides 10: 797-803 (1989); Grandt et al., Regul. Pept. 51: 151-9 (1994)). This fragment constitutes approximately 40% of total PYY-like immunoreactivity in human an! canine intestinal extracts and about 36% of total plasma PYY immunoreactivity in a fasting state to slightly over 50% following a meal. It is apparently a dipeptidyl peptidiise-IV (DPP4) cleavage product of PYY. PYY(3-36) is reportedly a selective ligand at (the Y2 and Y5 receptors, which appear pharmacologically unique in preferring N-terminally truncated (i.e., C-terminal fragments of) NPY analogs. Peripheral administration of YY reportedly reduces gastric acid secretion, gastric motility, exocrine pancreatic secretion (Yoshinaga et al., Am. J. Physiol. 263: G695-701 (1992); Guan et al, Endocrinology 128: 911-6 (1991); Pappas et al, Gastroenterology 91: 1386-9 (1986)), gallbladdei 166-70 (1987)). The effects . motility and gastric acid sec hindbrain/brainstem (Chen and Regul Pept. 61: 95-98 (1996) Chen et al, Neurogastroentero observed after peripheral injecl contraction and intestinal motility (Savage et al, Gut 28: 'f central injection of PYY on gastric emptying, gastric etion, as seen after direct injection in or around the Rogers, Am. J. Physiol 269: R787-92 (1995); Chen et al, Yang and Tache, Am. J. Physiol 268: G943-8 (1995); /. Motil 9: 109-16 (1997)), may differ from those effects on. For example, centrally administered PYY had some effects opposite to those described herein for peripherally injected PYY(3-36) in that gastric acid secretion was stirm dated, not inhibited. Gastric motility was suppressed only in conjunction with TRH stimulation, but not when administered alone, and was indeed stimulatory at higher doses through presumed interaction with PP receptors. PYY has been shown to stimulate food and water intake after central administration (Morley et al., Brain Res. 341: 200-3 (1985); Metabolic diseases and diso ders take on may forms, including obesity, diabetes, dyslipidemia, insulin resistance, cellular apoptosis, etc. Obesity and its associated disorders are common and very serious public health problems in the United States and throughout the world. Upper 1x>dy obesity is the strongest risk factor known for type 2 diabetes mellitus, and is a strong risk factor for cardiovascular disease. Obesity is a recognized risk factor for hypertension, atherosclerosis, congestive heart failure, stroke gallbladder disease, osteoarthrijtis, sleep apnea, reproductive disorders such as polycystic ovarian syndrome, cancers of pe breast, prostate, and colon, and increased incidence of i complications of general anesthesia (see, e.g., Kopelman, Nature 404: 635-43 (2000)). It reduces life-span and carries a serious risk of co-morbidities above, as well disorders such as infections, varicose veins, acanthosis nigricans, eczema, exercise intolerance, insulin resistance, hypertensioh hypercholesterolemia, cholelithiasis, orthopedic injury, and thromboembolic disease (FLissanen et al., Br. Med. J. 301: 835-7 (1990)). Obesity is also a risk factor for the group of conditions called insulin resistance syndrome, or "Syndrome X." Recent estimate for the medical cost of obesity and associated disorders is $150 billion worldwide. The pathogenesis of obesity is believed to be multifactorial but the basic problem is that in obese subjects nutrient availability and energy expenditure do not come into balance until there is excess adipose tissue. Obesity is currently a poorly treatable, chronic, essentially intractable metabolic disorder. A therapeutic drug useful in wejight reduction of obese persons could have a profound beneficial effect on their health Diabetes is a disorder of carbohydrate metabolism characterized by hyperglycemia and glucosuria resulting from insufficient production or utilization of insulin. Diabetes severely affects the quality of life of large parts of the populations in developed countries. Insufficient production of insulin is characterized as type 1 diabetes and insufficient utilization of insulin is type 2 diabetes. However, it is now widely recognized that there are many distinct diabetes related diseases which have their onset long before patients are diagnosed as having overt diabetes. Also, the effects from the suboptimal control of glucose metabolism in diabees gives rise to a wide spectrum of related lipid and cardiovascular disorders. Dyslipidemia, or abnormal levels of lipoproteins in blood plasma, is a frequent occurrence among diabetics. Dyslipidemia is typically characterized by elevated plasma triglycerides, low HDL (High ] Density Lipoprotein) cholesterol, normal to elevated levels of LDL (Low Density Lipoprotein) cholesterol and increased levels of small dense, LDL (Low Density Lipoprotein) piirticles in the blood. Dyslipidemia is one of the main contributors to the increased ncidence of coronary events and deaths among diabetic subjects. Epidemiologicai studies have confirmed this by showing a several-fold increase in coronary deaths among dial>etic subjects when compared with non-diabetic subjects j Several lipoprotein abnormalities have been described among diabetic subjects. Insulin resistance is the diminished ability of insulin to exert its biologically action across a broad range of concentrations. In insulin resistance, the body secretes abnormally high amounts of insulin to compensate for this defect and a state of impaired glucose tolerance develops. Failing to compensate for the defective insulin action, the plasma glucose Concentration inevitable rises resulting in the clinical state of diabetes. It is being recognized that insulin resistance and relative hyperinsulinemia have a contributory role in obesity, hypertension, atherosclerosis and type 2 diabetes. The association of insulin resistance with obesity, hypei tension and angina has been described as a syndrome, Syndrome X, having insulin resistance as the common pathogenic link. during normal development. It is well documented that regulation of pancreatic endocrine beta cells. There is Apoptosis is an active process i of cellular self-destruction that is regulated by extrinsic and intrinsic signals occurring apoptosis plays a key role in increasing evidence that in aiult mammals the beta-cell mass is subject to dynamic changes to adapt insulin production for maintaining euglycemia in particular conditions, such as pregnancy and obesity.The control of beta cell mass depends on a subtle balance between cell proliferation, growthand programmed cell death (apoptosis). A disturbance of this balance may lead to mpairment of glucose homeostasis. For example, it is noteworthy that glucose intolerance develops with aging when beta cell replication rates are reduced and human autop cell mass in patients with studies repeatedly showed a 40-60% reduction of beta non-insulin-dependent-diabetes mellitus compared with nondiabetic subjects. It is generally agreed that insulin resistance is an invariable accompaniment of obesity but that normoglycemia is maintained by compensatory hyperinsulinemia until the beti cells become unable to meet the increased demand forinsulin, at which point type 2 diabetes begins. Attempts to treatment of the multiple abnormalities associated with diabetes have prompted for the administration of several anti-diabetic medicaments in order to address these abnormalities in the different patients. Examples of anti-diabetic medicaments are proteins such as insulin and insulin analogues, and small molecules such as insulin sensitizers, insulin secretagogues and appetite regulating compounds. There remains a need to develop polypeptides to useful in the above described metabolic diseases, conditions, and disorders. Accordingly, it is an object of the present invention to provide hybrid polypeptides and methods for producing and using them. All documents referred to herein are incorporated by reference into the presen application as though fully set brth herein. SUMMARY OF THE INVENTION The present invention relates generally to novel, selectable hybrid polypeptides useful as agents for the treatment and prevention of metabolic diseases and disorders which can be alleviated by control plasma g ucose levels, insulin levels, and/or insulin secretion, such as diabetes and diabetes-related conditions. Such conditions and disorders include, bu are not limited to, hypertension, dyslipidernia, cardiovascular disease, eating disorders insulin-resistance, obesity, an diabetes mellitus of any kind, including type 1, type 2 and gestational diabetes. In one aspect of the invention, hybrid polypeptides exhibiting at least one hormonal activity are provided. The hybrid polypeptides of the invention comprise at least two bio-active peptide hormone modules covalently linked together, wherein at least one of the bio-active peptide hormone modules exhibits at least one hormonal activity of a component peptide hormon^. The bio-active peptide hormone modules are independently selected from: peptide hormones that exhibi component peptide hormones, fragments of component at least one hormonal activity of the component peptide component peptide hormones, fragments of analogs and de hormones that exhibit at least one hormonal activity ol hormones, analogs and deriva ives of component peptide hormones that exhibit at least one hormonal activity of the derivatives of component pept the component peptide hormones, and peptidic enhancers. Component peptide hormones of the invention include: amylin, adrenomedullin (ADM), calcitonin (CT), calcitonin gene related peptide (CGRP), intermedin, cholecystokinin ("CCK"), leptin, peptide YY (PYY), glucagon-like peptide-1 (GLP-1), glucagon-like peptide 2 (GLP-2), oxyntomodulin (OXM), and exendin-4; Peptidic enhancers of the in ention include: structural motifs of component peptide hormones that impart a desired chemical stability, conformational stability, metabolic stability, receptor interaction, to the hybrid polypeptide, and peptide hormones that impar rotease inhibition, or other pharmacokinetic characteristic structural motifs of analogs or derivatives of component a desired chemical stability, conformational stability, metabolic stability, receptor interaction, protease inhibition, or other pharmacokinetic characteristic to the hybrid pol peptide. In another aspect of the invention, methods for treating or preventing obesity are provided, wherein the method comprises administering a therapeutically or prophylactically effective amount of a hybrid polypeptide of the invention to a subject in need thereof. In a preferred embodiment, the subject is an obese or overweight subject. While "obesity" is generally def ined as a body mass index over 30, for purposes of this disclosure, any subject, including those with a body mass index of less than 30, who needs or wishes to reduce body are insulin resistant, glucose ir 1, 2 or gestational diabetes) car weight is included in the scope of "obese." Subjects who tolerant, or have any form of diabetes mellirus (e.g., type benefit from this method. In yet another aspect of the invsntion, methods of reducing food intake, reducing nutrient av ailability, causing weight oss, treating diabetes mellirus or diabetes-associated conditions, and improving Itpid profile (including reducing LDL cholesterol and triglyceride levels and/or charjging HDL cholesterol levels) are provided, wherein the methods comprise administering to a subject an effective amount of a hybrid polypeptide of the invention. In a preferred embodiment, the methods of the invention are used to treat or prevent conditions or disorders which can be alleviated by reducing nutrient availability in a subject in n:ed thereof, comprising administering to said subject a therapeutically or prophylacti sally effective amount of a hybrid polypeptide of the invention. In another embodiment, the methods of the invention are used to treat or prevent conditions or disorders which can be alleviated by control plasma glucose levels, insulin levels, and/or insulin s jcretion. In yet another embodiment, the methods of the invention are used to treat dia jetes and/or diabetes-related conditions. Such conditions and disorders include, but are not limited to, hypertension, dyslipidemia, cardiovascular disease, eating disorders, insulin-resistance, obesity, and diabetes mellitus of any kind, including Type I, Type II, anc gestational diabetes, diabetes complications (neuropathy (based on, e.g., neurotrophic actions of exendin-4), neuropathic pain (based on, e.g., amylin action), retinopathy, mphropathy, conditions of insufficient pancreatic beta cell mass (based on, e.g., islet neog;nesis actions of exendin-4 and GLP-1). The present invention also relates to pharmaceutical compositions comprising a therapeutically or prophylactically effective amount of at least one hybrid polypeptide of the invention, or a phanaaceutically acceptable salt thereof, together with pharmaceutically acceptable d and/or carriers useful in the del These and other aspects of the luents, preservatives, solubilizers, emulsifiers, adjuvants very of the hybrid polypeptides. invention will be more clearly understood with reference to the following preferred embodiments and detailed description. I BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 demonstrates the effect of exemplary compounds of the invention in DIO mouse assay. Figure 2 demonstrates the effect of exemplary compounds of the invention in DIO mouse assay. Figures 3A-3B demonstrates th|e effect of exemplary compounds of the invention in DIO mouse assay. Figure 4A-4B demonstrates the effects of exemplary compounds of the invention in fooi intake assay, compared to parent peptide compounds. DETAILED DESCRIPTION OF THE INVENTION The present invention relates generally to novel, selectable hybrid polypeptides useful a agents for the treatment and prevention of metabolic diseases and disorders which can be alleviated by control plasma g ucose levels, insulin levels, and/or insulin secretion, such as diabetes and diabetes-related conditions. Such conditions and disorders include, bu are not limited to, hypertension, dyslipidemia, cardiovascular disease, eating disorders insulin-resistance, obesity, and diabetes mellitus of any kind, including type 1, type 2 and gestational diabetes. metabolically, and/or pharmaci based on "bio-activities", e.g., In one aspect, the invention involves the modular assembly of physiologically kinetically active peptidic modules that may be selectable therapeutic efficacy, scope of function, duration of action physicochemical properties, and/or other pharmacokinetic properties. Without intending to be limited by theory, the present invention relates at least in part to a "toolbox" approach, wherein bio-active peptide hormone modules are linked in binary tertiary or higher order combinations to create novel, efficacious therapeutic agents with selectable properties. The ' hormones, peptide fragments bio-active peptide hormone modules" may be peptide with hormonal activity, or structural motifs of peptide hormones that impart chemical, metabolic, and/or other pharmacokinetic stability. The peptide hormones can include native peptide hormones, as well as peptide hormone analogs and derivatives, as kncwn in the art and described herein. In one aspect of the invention, it has been found that the combination of certain physicochemical characteristics of two or more peptide hormones into a single modality can facilitate intervention at several points in a dysfunctional metabolic circuit. As such, in one aspect of the invention, rationally-designed hybrid polypeptides are provided that integrate selectable bio-activities into a single polypeptide agent. In one embodiment, the selectable hybrid p olypeptides linkers to covalently attach of the invention may involve the use of chemically stable the bio-active modules. In another embodiment, theSel ectable hybrid polypeptides of the invention may involve the use of cleavable linkers which themselves may be or fcrm part of a bio-active module. Again, without intending to be limited by theory, design of the hybrid polypeptides of th present invention may generally involve: (1) the identification, selection and pairing o bio-active peptide hormone modules for desired efficacy and therapeutic use, and (2) th covalent linking of the bio-jctive modules (e.g. native peptide hormones, peptid hormone analogs or derivatives with hormonal activity, peptide hormone fragments with hormonal activity, stabilizing notifs, etc.) either directly or via a linker without loss o bio-activity of the componert modules. In certain embodiments, module selection criteria may include, but not be limited to: (a) desired in vivo efficacy for desired therapeutic or prophylactic indication; (b) optional synergism or dual action of the linkec modules for multiple therapeutic or prophylactic indications; and/or (c) a desirec chemical stability, conformational stability, metabolic stability, receptor interaction protease inhibition, and/or other pharmacokinetic characteristic. The section headings are used herein for organizational purposes only, and are not to be construed as in any way limiting the subject matter described. Hybrid Polvpeptides of the Invention As mentioned above, the piesent invention relates in part to hybrid polypeptides comprising at least two bio-ac ive peptide hormone modules selectable from componen peptide hormones described herein. The hybrid polypeptides of the present invention will generally be useful in tl treatment and prevention of metabolic conditions am disorders. The hybrid polype slides of the invention will exhibit at least one hormona activity of a component pepiide hormone, and may preferably include at least one additional bio-activity of a second component peptide hormone. In one embodiment, the hybrid polypeptides of the invention may comprise at least two bio-active peptide hormone modules, wherein each of said at least two bio-active peptide hormone modules exhibits a least one hormonal activity of a component peptide hormone. In another embodiment, the hybrid polypeptides of the invention may comprise at least two bio-active peptide hormone modules, wherein at least one of saic bio-active peptide hormone component peptide hormone imparts a desired chemical sta interaction, protease inhibition, polypeptide. In a preferred embodiment, comparable or higher potency and disorders, as compared to the hybrid polypeptides of the treatment and/or prevention the component peptide invention may exhibit im] formulation, as compared to th More particularly, the hybri The first bio-active peptide hi peptide hormone, and may be well as analogs and derivath (including fragments of nativi thereof), or a structural motif o well as analogs and derivati conformational stability, and/or other pharmacokinetic additional bio-active peptide aid modules exhibits at least one hormonal activity of at least one of said bio-active peptide hormone modules ility, conformational stability, metabolic stability, receptor and/or other pharmacokinetic characteristic to the hybric hormcnes .proved the hybrid polypeptides of the invention may have n the treatment and/or prevention of metabolic conditions he component peptide hormones. In another embodiment, invention may have comparable or higher potency in the oil diabetes and/or diabetes-related disorders, as compared to Alternatively, preferred hybrid polypeptides of the ease of manufacture, stability, and/or ease oi component peptide hormones. peptide polypeptides of the present invention will generally ide hormone module covalently linked to at least one irmone module. The bio-active peptide hormone modules ther in any manner known in the art, including but not or chemical linker groups, as described in further detail emical linker groups may include peptide mimetics which conformation. metabolic module may be selected from a first component peptide hormone (including native peptide hormones as es thereof), a peptide fragment with hormonal activity peptides hormones as well as analogs and derivatives a peptide hormone (including native peptide hormones as es thereof) that imparts a desired chemical stability, stability, receptor interaction, protease inhibition, characteristic to the hybrid polypeptide. Likewise, the module(s) may be selected from component peptide stability, metabolic stability, pharmacokinetic characteristic the additional peptide hormone hormones, and may be a peptide hormone (including native peptide hormones as well as analogs and derivatives thereof), a peptide fragment with hormonal activity (including fragments of native peptides hormones as well as analogs and derivatives thereof), or a structural motif of a hormon receptor interaction, protease inhibition, and/or other to the hybrid polypeptide. The first peptide hormone and may be the same peptide hormone, may be from the same family of peptide hormones, or may be different peptide hormones, depending on the desired characteristics of the bio-active peptide hormone modules. As used herein, the term "bio-active" refers to (1) biological activity in at least one in vivo hormonal pathway, or (2) modulation of the therapeutic efficacy, scope of function, duration of action, physicochemical properties, and/or other pharmacokinetic properties of such biological activity. Biological activity may be evaluated through target hormone receptor binding assays, or through metabolic studies that monitor a physiological indication, as known in the art and described herein. Modulation of the therapeutic efficacy, scope of function, duration of action, physicochemical properties, and/or other pharmacokinetic properties of such biological activity may be modified through changed in, e.g., chemical stability, conformational stability, metabolic stability, receptor interaction, protease inhibition, and/or other pharmacokinetic characteristics. In one embodiment, the hybrki polypeptides of the invention retain at least about 25%, preferably about 30%, 40%, 5(1%, 60%, 70%, 80%, 90%, 95%, 98%, or 99% percent of the biological activity of a cotiponent peptide hormone. Preferred hybrid polypeptides are those having a potency in one of the metabolic-related assays known in the art or described herein (e.g., receptor binding, food intake, gastric emptying, pancreatic secretion, insulin secretion, blood glucose lowering, weight reduction, etc.) which is equal to or greater than the potency of component peptide hormone in that same assay. Alternatively, preferred hybrid polypeptides of the invention may exhibit improved ease of manufacture, stability, and/or ease of formulation, as compared to component peptide hormones. In another embodiment, the hybrid polypeptides of the invention retain at least abou 25%, preferably about 30%, W%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, or 99°/ percent of the biological activity of a native component peptide hormone with regard t the reduction of nutrient aval weight gain, and/or the treatm ability, the reduction of food intake, the effect of bod) ;nt and prevention of metabolic conditions and disorders In yet another embodiment, the hybrid polypeptides of the invention exhibit at least abou 110%, 125%, 130%, 140%, II10%, 200%, or more of the biological activity of a nativ peptide hormone with regard tc the reduction of nutrient availability the reduction of foot intake, the effect of body weight gain, and/or the treatment and prevention of metabolic conditions and disorders. In another embodiment, the hybrid polypeptides of thi invention exhibit improved component peptide hormone receptor agonist activity. i Component Peptides Hormones, Analogs and Derivatives Component peptide hormones generally include peptide hormones useful in the treatmen or prevention of metabolic diseases and disorders including: (a) the amylin family including amylin, adrenomedi llin ("ADM"), calcitonin ("CT"), calcitonin gene related peptide ("CGRP"), interned cholecystokinin ("CCK"); (c) i (also known as "AFP-6") and related peptides; (b he leptin family, including leptin and leptin-like peptides (d) the pancreatic polypeptide family, including pancreatic polypeptide ("PP") anc hormones derived from the prc glucagon gene such as: glucagon, glucagon-like peptide-1 ("GLP-1"), glucagon-like pejitide 2 ("GLP-2"), and oxyntomodulin ("OXM"); and peptide YY ("PYY"); and exendins such as: exendin-3, hormones of the invention al activity of these native pept e) incretins and incretin mimetics, including: peptide and exendin-4. As discussed above, component peptide so include analogs and derivatives that retain hormona de hormones. In one embodiment, such analogs and derivatives are agonists of the target hormone receptor. By "amylin" is meant the human peptide hormone referred to as amylin and secreted from the beta cells of the pan reas, and species variations thereof, as described in U.S Pat. No. 5,234,906, issued Aug. 10, 1993, for "Hyperglycemic Compositions," the contents of which are hereby ncorporated by reference. More particularly, amylin is a 37-amino acid polypeptide hoitmone normally co-secreted with insulin by pancreatic bets cells in response to nutrient intake (see, e.g., Koda et al., Lancet 339:1179-1180, 1992 In this sense, "amylin," "wi amylin, are used interchangeal d-type amylin," and "native amylin," i.e., unmodifiey- By "adrenomedullin" or "ADM" is meant the human peptide hormone and specie variants thereof. More particularly, ADM is generated from a 185 amino aci preprohormone through cons« culminates in the liberation of cutive enzymatic cleavage and amidation. This proces 52 amino acid bioactive peptide. By "calcitonin" or "CT" is meant the human peptide hormone and species variants thereof, including salmon calcitonin ("sCT"). More particularly, CT is a 32 amino aci peptide cleaved from a larger causes the amino terminus to prohormone. It contains a single disulfide bond, which assume the shape of a ring. Alternative splicing of th calcitonin pre-mRNA can yield a mRNA encoding calcitonin gene-related peptide; tha peptide appears to function in (the nervous and vascular systems. The calcitonin recepto has been cloned and shown o be a member of the seven-transmembrane, G protein coupled receptor family. By "calcitonin gene related peptide" or "CGRP" is meant the human peptide hormom and species variants thereof, in By "intermedin" or "AFP-6" any physiological form. s meant the human peptide hormone and species variant! thereof, in any physiological form. By "cholecystokinin" or "CCK" is meant the human peptide hormone and species variants thereof. More particularly, CCK is a 33-amino acid sequence first identified ir humans, and includes a 8-am been reportedly demonstrated no acid in vivo C-terminal fragment ("CCK-8") that has n pig, rat, chicken, chinchilla, dog and humans. Thus, the trm CCK-33 will generally refcr to human CCK(l-33), while CCK-8 (CCK(26-33)) wil refer to the C-terminal octapeptide generically in both the sulfated and unsulfated unles: ! otherwise specified. Further, jsentagastrin or CCK-5 will refer to the C-terminal peptide CCK(29-33), and the CCK-4 will refer to the C-terminal tetrapeptide CCK(30-33) However, as used herein, CCKJ will generally refer to all naturally occurring variations the hormone, including CCK unsulfated form unless otherwise -33, CCK-8, CCK-5, and CCK-4, in the sulfated anc se specified. By "leptin" is meant the biologically active D-isoform thereof, and combinations of gene as described in the incorporated herein by referen are reported in US Patent 5 PCT/US96/01471, each of whi By "PP" is meant human pan any physiological form. Thu amino acid peptide as set forth e.g., murine, hamster, chicken PP," and "native PP," i.e., unmodified By "PYY" is meant human peptide physiological form. Thus, the acid peptide, and species variations bovine, rat, and dog PYY. In this i.e., unmodified PYY, are use By "GLP-1" is meant human physiological form. The term GLP-1 (7-36)amide, with refei variations of GLP-1, includinj In this sense, "GLP-1," "wild-are used interchangeably. Intel national .turally occurring leptin from any species, as well as , or fragments of naturally occurring leptin and variants preceding. Leptin is the polypeptide product of the ob Patent Publication No. WO 96/05309, which i ;e in its entirety. Putative analogs and fragments of leptin 521,283, U. S. Patent 5,532,336, PCT/US96/22308 and ;h is incorporated herein by reference in its entirety. ;reatic peptide polypeptide or species variants thereof, in , the term "PP" includes both the human full length, 36 in SEQ ID NO: 1, and species variations of PP, including bovine, rat, and dog PP. In this sense, "PP," "wild-typ PP, are used interchangeably. YY polypeptide or species variants thereof, in anj erm "PYY" includes both the human full length, 36 amino of PYY, including e.g., murine, hamster, chicken, lis sense, "PYY" and "wild-type PYY" and "native PYY,' interchangeably. In the context of the present invention h reference to the PYY analog polypeptides of the presen acid sequence of native human PYY. lucagon like peptide-1 or species variants thereof, in any 'GLP-1" includes human GLP-l(l-37), GLP-l(7-37), and ence to the full length human GLP-l(l-37), and species e.g., murine, hamster, chicken, bovine, rat, and dog PP e GLP-1," and "native GLP-1," i.e., unmodified GLP-1 By "GLP-2" is meant human physiological form. More along with GLP-1 from intest: By "OXM" is meant humin physiological form. More particularly 29 amino acid sequence of extension. glucagon like peptide-2 or species variants thereof, in an pa ticularly, GLP-2 is a 33 amino acid peptide, co-secrete lal endocrine cells in the small and large intestine. oxyntomodulin or species variants thereof in an , OXM is a 37 amino acid peptide that contains th ;lucagon followed by an 8 amino acid carboxytermina By "exendin" is meant a pepti endogenous to Arizona, and thereof. More particularly, E and exendin-4 is present in th Chem., 265:20259-62, 1990; exendins have some sequence family, with the highest iden 268:19650-55 (1993)). In exendin," i.e., unmodified exe e hormone found in the saliva of the Gila-monster, a lizan the Mexican Beaded Lizard, as well as species variant endin-3 is present in the saliva of Heloderma horridum saliva of Heloderma suspectum (Eng, J., et al, J. Biol ng., J., et al., J. Biol. Chem., 267:7402-05 (1992)). Tb similarity to several members of the glucagon-like peptide ty, 53%, being to GLP-1 (Goke, et al, J. Biol. Chem. tiis sense, "exendin," "wild-type exendin," and "nativ idin, are used interchangeably. As used herein, an "analog" re a base reference peptide (e. insertions, substitutions, sequence, preferably having base peptide, more preferabl sequence identity with the has conservative or non-conservat acids and L and D forms). A "derivative" is defined as reference peptide or analog, more of its amino acid side carboxylic acid group. A chemical moieties, creating ers to a peptide whose sequence was derived from that o ., PP, PYY, amylin, GLP-1, exendin, etc.), including extensions, and/or deletions of the reference amino acic least 50 or 55% amino acid sequence identity with the having at least 70%, 80%, 90%, or 95% amino acic peptide. In one embodiment, such analogs may comprise ve amino acid substitutions (including non-natural aminc new molecule having the amino acid sequence of a native ut additionally having chemical modification of one 01 gtoups, a-carbon atoms, terminal amino group, or termina chqmical modification includes, but is not limited to, adding bonds, and removing chemical moieties. Modification: at amino acid side groups incl N-alkylation of arginine, histi acid groups, and deamidation amino include, without lim constrained alky Is (e.g. bran By "agonist" is meant a com reference peptide, preferably h five orders of magnitude (plui more preferably 4, 3, 2, or 1 o such as receptor binding/com compound which elicits a bi peptide, for example a pancreatic secretion, or weigh (2) which binds specifically i assay with labeled reference with an affinity of greater than 1-5 nM. In another embodiment effect in the treatment of dii agonists may comprise a po peptide or a small chemical m By "amino acid" and "amino acids, and modified amino aci acid, generally or specifically stereoisomers if their structur ide, without limitation, acylation of lysine e-amino groups ine, or lysine, alkylation of glutamic or aspartic carboxyli )f glutamine or asparagine. Modifications of the termina ation, the desamino, N-lower alkyl, N-di-lower alky led, cyclic, fused, adamantyl) and N-acyl modifications arboxy group include, without limitation, the amide, lowe s (e.g. branched, cyclic, fused, adamantyl) alkyl, dialky lodifications. Lower alkyl is C1-C4 alkyl. Furthermore terminal groups, may be protected by protective group peptide chemist. The a-carbon of an amino acid may be compoi nd (1) having; ound which elicits a biological activity of native humar iving a potency better than the reference peptide, or within or minus) of potency compared to the reference peptide der of magnitude, when evaluated by art-known measures etition studies. In one embodiment, the terms refer to e logical effect similar to that of native human reference activity in the food intake, gastric emptying loss assays similar to native human reference peptide, o a reference receptor assay or in a competitive binding . Preferably, the agonists will bind in such assays I uM, and more preferably with an affinity of greater than it, the terms refer to a compound which elicits a biologicaL)etes or a diabetes related condition or disorder. Such ypeptide comprising an active fragment of a reference ecule. acid residue" is meant natural amino acids, unnatural aminc Unless stated to the contrary, any reference to an aminc by name, includes reference to both the D and the L allow such stereoisomeric forms. Natural amino acids and aanme include alanine (Ala), argini (Cys), glutamine (Gin), (He), leucine (Leu), Lysine (L serine (Ser), threonine (Thr Unnatural amino acids inclu azetidinecarboxylic acid, aminopropionic acid, 2-aminobu aminoheptanoic acid, 2aminoi tertiary-butylglycine, 2,4-diarn 2,3-diaminopropionic acid, hydroxylysine, allo-hydroxyl) allo-isoleucine, N-methylaline methylpentylglycine, N-methyl pentylglycine, pipecolic acid modified amino acid residues chemically modified on their example, N-methylated D functional groups are chemiall modified amino acids include (beta-methyl ester), a modifie amino acid of glycine; or Additional residues that can t Chem. 41:2481-91,1998. e (Arg), asparagine (Asn), aspartic acid (Asp), cystein ic acid (Glu), glycine (Gly), histidine (His), isoleucin fs), methionine (Met), phenylalanine (Phe), proline (Pro) , tryptophan (Trp), tyrosine (Tyr) and valine (Val) e, but are not limited to homo-lysine, homo-arginine aminoadipic acid, 3-aminoadipic acid, beta-alanine utyric acid, 4-aminobutyric acid, 6-aminocaproic acid, 2 obutyric acid, 3-aminoisbutyric acid, 2-aminopimelic acid noisobutyric acid, desmosine, 2,2'-diaminopimelic acid N-ethylglycine, N-ethylasparagine, homoproline ine, 3-hydroxyproline, 4-hydroxyproline, isodesmosine mine, N-methylglycine, N-methylisoleucine, N valine, naphthalanine, norvaline, norleucine, ornithine and thioproline. Additional unnatural amino acids include which are chemically blocked, reversibly or irreversibly, o; -terminal amino group or their side chain groups, as foi L amino acids or residues wherein the side chain ly modified to another functional group. For example methionine sulfoxide; methionine sulfone; aspartic acid- amino acid of aspartic acid; N-ethylglycine, a modified carboxamide, a modified amino acid of alanine incorporated are described in Sandberg et al., J. Med As used herein: "5 Apa" dodecanoyl, "PEG(8)" mean: tioxa-13-tridecanamine succin moyl gieans 5 amino-pentanoyl, "12 Ado" means 12-aminc 6,-dioxyoctanoyl, and "PEG(13)" means l-amino-4,7,10- As discussed above, native analogs and derivatives. Fo peptide hormones are providec Table 1:E> component peptide hormones are known in the art, as are theii reference, the sequences of several native componem below in Table 1. mplary Component Peptide Hormones (Table Removed) Exendin-3: HSDGTFFSDL SKQMEEEAVR LFIEWLKNGG PSSGAPPPS 66 Exendin-4 HGEGTFrSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS These peptides are generally need not be for the purposes these peptides, as well as the free -OH or -NH2 group, modifications. One skilled in present invention may also be The analogs of the above c generally include modificatio amino acid sequence of such The substitutions, insertions ar may be at internal portions o analogs of the component p modifications of a "non-essen "non-essential" amino acid r substituted, in the native h component peptide hormone component peptide hormone n Preferred substitutions incluc amino acid substitution" is one acid residue having a simil electrostatic, hydrogen bondin residues having similar side c acids with basic side chains aspartic acid, glutamic acid), glutamine, serine, threonine, alanine, valine, leucine, i -terminally amidated when expressed physiologically, bu f the instant invention. In other words, the C-terminus o hybrid polypeptides of the present invention, may have These peptides may also have other post-translationa the art will appreciate that the hybrid polypeptides of th onstructed with an N-terminal methionine residue. mponent peptide hormones are known in the art, bu is such as substitutions, deletions, and insertions to th conserved amino acid substitutions. A "conservative .n which the amino acid residue is replaced with an amino x side chain, or physicochemical characteristics (e.g. isosteric, hydrophobic features). Families of amino acic ains are known in the art. These families include aminc .g., lysine, arginine, histidine), acidic side chains (e.g. uncharged polar side chains (e.g., glycine, asparagine tjyrosine, methionine, cysteine), nonpolar side chains (e.g. , proline, phenylalanine, tryptophan), p-branched side isolei cine chains (e.g., threonine, valin phenylalanine, tryptophan, his The present invention also Such derivatives include com one or more water soluble po fatty acid chains of various addition of polyamino acic Modifications to the compon small molecule substituents, s cyclic, fused, adamantyl), and will preferably have a molecul ir :, isoleucine) and aromatic side chains (e.g., tyrosine idine). relates to derivatives of the component peptide hormones onent peptide hormones and analogs thereof conjugated t ymer molecules, such as polyethylene glycol ("PEG") o ngths (e.g., stearyl, palmitoyl, octanoyl, etc.), or by thi , such as poly-his, poly-arg, poly-lys, and poly-ala nt peptide hormones or analogs thereof can also includ jch as short alky Is and constrained alkyls (e.g., branched aromatic groups. The water soluble polymer molecule; weight ranging from about 500 to about 20,000 Daltons. Such polymer-conjugations a singularly at the N- or C-sequence of the hybrid poly derivatization along the hybn with lysine, aspartic acid, gl derivatization. See, e.g., U.S hybrid polypeptides may The water soluble polymer me group, and may be linked by acid, glutamic acid, or cystein be linked with diamine and di polypeptides of the invention an epsilon amino group on a 1> Derivatives of the invention chemical alterations to one c include amidation, glycosylati cyclization. The chemical altt the side chains of amino terminus be conjugated id small molecule substituent modifications may occui or at the side chains of amino acid residues within theptides. Alternatively, there may be multiple sites o polypeptide. Substitution of one or more amino acids i|tamic acid, or cysteine may provide additional sites fo Patent Nos. 5,824,784 and 5,824,778. Preferably, the to one, two, or three polymer molecules. ecules are preferably lined to an amino, carboxyl, or thio M or C terminus, or at the side chains of lysine, aspartic are Alternatively, the water soluble polymer molecules ma> arboxylic groups. In a preferred embodiment, the hybric conjugated to one, two, or three PEG molecules through ine amino acid. allso include component peptide hormones or analogs with more amino acid residues. Such chemical alteration: n, acylation, sulfation, phosphorylation, acetylation, anc ations may occur singularly at the N- or C-terminus or a 4 id residues within the sequence of the PPF hybric polypeptides. In one embodir or -NHj group. In another isobutyloxycarbonyl group, group, an ethoxycarbonyl glycine group (G(Oct)), or ar cyclization can be through the multiple sites of chemical The Amvlin Family As discussed above, compone amylin family peptide hormo ("CT"), calcitonin gene relate and related peptides. Native functional peptide analogs analogs and derivatives are d known amylin family peptide used in conjunction with the p Any amylin analog or present invention. In one em one hormonal activity of nativ agonists of a receptor which amylin analogs and derivative; hereby incorporated by referen Exemplary amylin analogs incent, the C-terminus of these peptides may have a free -OKnbodiment, the N-terminal end may be capped with ain isopropyloxycarbonyl group, an n-butyloxycarbony groip, i, an isocaproyl group (isocap), an octanyl group, an octy 8-aminooctanic acid group. In a preferred embodimen formation of disulfide bridges. Alternatively, there may be alteration along the hybrid polypeptide. t peptide hormones useful in the present invention includ es including amylin, adrenomedullin ("ADM"), calcitonir peptide ("CGRP"), intermedin (also known as "AFP-6" unylin family peptide hormones are known in art, as arc and derivatives. Certain preferred native peptides, peptid scribed herein, however it should be recognized that anj that exhibit hormonal activity known in the art may be esent invention. derivat ve known in the art may be used in conjunction with th odiment, the amylin analogs and derivatives have at leas amylin. In certain embodiments, the amylin analogs are rjative amylin is capable of specifically binding. Preferrec include those described in US 2003/0026812 Al, which is e. ude: (Table Removed) CCKs, including hCCK and the art. Generally, CCK has includes a 8-amino acid in vi demonstrated in pig, rat, chi include a 39-amino acid sequ found in cat, dog and humans and gastrin. The C-termin 1 conserved across species, and periphery of rodents. Thus, th while CCK-8 (CCK(26-33)) the sulfated and unsulfated will refer to the C-terminal terminal tetrapeptide CCK(30- The type A receptor subtype octapeptide. The Type B rei brain and in the stomach, an acids. >ecies variants, and various analogs thereof are known i 33-amino acid sequence first identified in humans, an C-terminal fragment ("CCK-8") that has been reportedl ten, chinchilla, dog and humans. Other species varian ice found in pig, dog and guinea pig, and a 5 8-amino aci and a 47-amino acid sequences homologous to both CCK sulfated octapeptide sequence (CCK-8) is relativel nay be the minimum sequence for biological activity in th term CCK-33 will generally refer to human CCK(l-33 urless ill refer to the C-terminal octapeptide generically in bot otherwise specified. Further, pentagastrin or CCK- eptide CCK(29-33), and the CCK-4 will refer to the C 3). has been reported to be selective for the sulfate Various in vivo and in vitro s Examples include in vivo as gallbladder after rapid intrave activity, and in vitro assays "Gastrointestinal Hormones", Raven Press, New York). Certain preferred CCKs and C reening methods for CCK analogs are known in the art ays involving the contraction of the dog or guinea pi ous injection of the compound to be tested for CCK-lik K analogs with CCK activity include: WMDF SEQ ID: 141 142 143 144 145 146 DY(SO3H)MG\fMDF DYMGWMDF MGWMDF GWMDF WMDF KDY(SO3H)MC 147 KDYMGWMDJ 148 KMGWMDF 149 KGWMDF 150 KWMDF As known in the art, such CCK peptides are preferably amidated, but within the conte of the present invention, may optionally be in the acid form unless otherwise specified. The Leptin Family Component peptide hormones useful in the present invention also include leptin famil peptide hormones. Native Uptin family peptide hormones are known in art, as ar functional peptide analogs ani derivatives. Certain preferred native peptides, peptid analogs and derivatives are d known amylin family peptide scribed herein, however it should be recognized that an that exhibit hormonal activity known in the art may b used in conjunction with the pi esent invention. Any leptin analog or derivati e known in the art may be used in conjunction with th present invention. In one embodiment, the leptin analogs and derivatives have at leas one hormonal activity of native leptin. In certain embodiments, the leptin analogs ar agonists of a receptor which native leptin is capable of specifically binding. Preferre leptin analogs and derivatives include those described in, e.g., WO 2004/039832, WC 98/55139, WO 98/12224, anjl WO 97/02004, all of which is hereby incorporated b reference. Exemplary leptin analogs incli ide those where the amino acid at position 43 is substitute with Asp or Glu; position 48 is substituted Ala; position 49 is substituted with Glu, o absent; position 75 is substituted with Ala; position 89 is substituted with Leu; positio 93 is substituted with Asp 01 substituted with Ser, position Glu; position 98 is substituted with Ala; position 117 i 39 is substituted with Leu, position 167 is substituted wit Ser, and any combination thereof. Certain preferred CCKs and CCK analogs with CCK activity include: SEQ ID: 151 152 153 Asp-leptin 3Glu-leptin Ala-leptin Component peptide hormones hormones, including PP and P functional peptide analogs analogs and derivatives are known amylin family peptide! used in conjunction with the Any PPF analog or derivativ In one embodiment, preferred hormonal activity generally motif and C-terminal tail motii Application No. 60/543,406 f reference. Other preferred PP an 1 useful in the present invention also include PPF peptide . Native PPF peptide hormones are known in art, as are derivatives. Certain preferred native peptides, peptide described herein, however it should be recognized that any that exhibit hormonal activity known in the art may be pijesent invention. known in the art may be used in conjunction with the embjxliment, the PPF analogs and derivatives have at least one flPF polypeptide. In certain embodiments, the PPF analogs \\ihich native PPF polypeptide is capable of specifically analogs and derivatives include those described in WO 5, which are herein incorporated by reference in their PPF analogs and derivatives that exhibit at least one PPF comprise at least two PYY motifs including a polyproline Such analogs are generally described in U.S. Provisional led February 11, 2004, which is herein incorporated by ' analogs are disclosed in PCT/US05/[XXXXX], entitled "Pancreatic Polypeptide Far Attorney Docket 18528.832, incorporated by reference, differences in Y receptor bin structural differences. See, e. porcine PYY has been charac residues 17 to 22 and 25 to centered around residues 12 Further, full-length porcine stabilized by hydrophobic inte A "PYY motif is generally a native PP family polypeptide is substantially decreased in motifs include the N-terminal the type II p-tum motif of ns terminal end of native PP fam family polypeptide. More pan corresponding to residues 5 conserved as a proline. The corresponding to residues 12-can generally extend from native PP family polypeptide t as the a-helical motif includes helical turn is formed in sol substitutions, insertions and d lily Motifs and Polypeptides Comprising the Same' led concurrently herewith, the contents of which is hereb Jy way of background, research has suggested that th ling affinities are correlated with secondary and tertiarj ., Keire el al., Biochemistry 2000, 39, 9935-9942. Nativ erized as including two C-terminal helical segments from 3 separated by a kink at residues 23, 24, and 25, a turr 4, and the N-terminus folded near residues 30 and 31 *YY has been characterized as including the PP fold, actions among residues in the N- and C- termini. See id. structural component, primary, secondary, or tertiary, of £ hat is critical to biological activity, i.e., biological activity absence or disturbance of the motif. Preferred PYY x)lyproline type II motif of a native PP family polypeptide ive PP family polypeptide, the a-helical motif at the C ly polypeptide, and the C-terminal tail motif of native PF cularly, in the N-terminal polyproline region, amino acids and 8 of a native PP family polypeptide are general!) type II p-turn motif will generally include amino acids ammo 4 of a native PP family polypeptide. The a-helical moti acids corresponding to approximately residue 14 of £ any point up to and including the C-terminal end, so long a sufficient number of amino acid residues such that an a-tion. The a-helical motif can also include amino acic etions to the native PP family sequence, so long as the a-ution. The C-terminal tail motif generally includes aminc ximately the last 10 residues of a native PP familj the last 7, 6, or 5 residues of a native PP familj y amino acid residues 32-35. Preferred PYY analogs incluc in areas of the PYY molecul terminal tail motif. For instance envisioned. those with internal deletions, insertions, and substitutions not corresponding to the polyproline motif and/or the C , internal deletions at positions 4, 6, 7, 9, or 10 ar Incretins and Incretm Mimetic Component peptide hormones hormones. Native GLP-1 GLP-1 (7-36)amide, are knowi As used herein, GLP-1 refers preferred native peptides, pep it should be recognized that known in the art may be used Any GLP-1 peptide analog o with the present invention, derivatives have at least one embodiments, the GLP-1 pepti|d' peptide is capable of speci derivatives include those desc by reference. GLP-1 analogs known in the a peptid useful in the present invention also include GLP-1 peptid ide hormones, including GLP-l(l-37), GLP-1 (7-37), an in art, as are functional peptide analogs and derivatives to all native forms of GLP-1 peptide hormones. Certair de analogs and derivatives are described herein, howeve ny known GLP-1 peptides that exhibit hormonal activit i conjunction with the present invention. derivative known in the art may be used in conjunctior In one embodiment, the GLP-1 peptide analogs anc lormonal activity of a native GLP-1 peptide. In certain e analogs are agonists of a receptor which a native GLP-cally binding. Preferred GLP-1 peptide analogs anc bed in, e.g., WO 91/11457, which is hereby incorporated include: As known in the art, such GLP-1 analogs may preferably be amidated, but within the context of the present inventi :>n, may optionally be in the acid form unless otherwise specified. Other GLP-1 analogs and derivatives are disclosed in U.S. Pat. No. 5,545,618 which is incorporated herein by reference. A preferred group of GLP-1 analogs and derivatives include those disclosed in U.S. Patent No. 6,747,006, which is herein incorporated by reference in its entirety. The use in the present invention of a molecule described in U.S reference. Another preferred group of GLP-1 compounds for use in the present invention is disclosed in WO 91/11457, which is herein incorporated by reference. Pat. No. 5,188,666, which is Another group of molecules described in U.S. Pat. No.xpressly incorporated by reference, is also contemplated for use in the present invention includes compounds 5,512,549, which is expressly incorporated herein by Component peptide hormones useful in the present invention also include GLP-2 peptide hormones. Native GLP-2 peptide hormones, e.g., rat GLP-2 and its homologous including ox GLP-2, porcine hamster GLP-2, human GLP-: GLP-2, degu GLP-2, bovine GLP-2, guinea pig GLP-2, , rainbow trout GLP-2, and chicken GLP-2, are known in art, as are functional peptide aialogs and derivatives. Certain preferred native peptides, peptide analogs and derivatives are described herein, however it should be recognized that any known GLP-2 peptides that exhibit hormonal activity known in the art may be used in conjunction with the prssent invention. Any GLP-2 peptide analog or with the present invention. derivative known in the art may be used in conjunction In one embodiment, the GLP-2 peptide analogs and derivatives have at least one hormonal activity of a native GLP-2 peptide. In certain embodiments, the GLP-2 peptile analogs are agonists of a receptor which a native GLP-2 peptide is capable of specif cally binding. Preferred GLP-2 peptide analogs and derivatives include those described in, e.g., U.S. Ser. No. 08/669,791 and PCI Application PCT/CA97/0025; , both of which are hereby incorporated by reference Specific GLP-2 analogs known in the art include: rat or human GLP-2 altered at position 2 to confer DPP-IV resistance )y substituting a Gly for an Ala. Component peptide hormones useful in the present invention also include oxyntomodulin (OXM) peptide hormones. Native OXM peptide hormones are known in art, as are functional peptide analogs and derivatives. Certain preferred native peptides, peptide analogs and derivatives are described herein, however it should be recognized that any known OXM peptides that exhibit hormonal activity known in the art may be used in conjunction with the present invention. Any OXM peptide analog or c the present invention. In one have at least one hormonal ac the OXM peptide analogs arc capable of specifically binding Component peptide hormone jrivative known in the art may be used in conjunction withembodiment, the OXM peptide analogs and derivativesivity of a native OXM peptide. In certain embodiments,agonists of a receptor which a native OXM peptide is useful in the present invention also include exendin peptide hormones. Native exendin peptide hormones are known in art, as are functional peptide analogs and derivatives. Certain preferred native peptides, peptide analogs and derivatives are described her sin, however it should be recognized that any known exendin peptides that exhibi conjunction with the present in Any exendin peptide analog o with the present invention. hormonal activity known in the art may be used in mention. derivative known in the art may be used in conjunction In one embodiment, the exendin peptide analogs and derivatives have at least one r ormonal activity of a native exendin peptide. In certain embodiments, the exendin pe exendin peptide is capable of s tide analogs are agonists of a receptor which a native iccifically binding. Preferred exendin analogs inchde: SEQ ID: 185 Leu, 3Phe-exe idin-4 (Table Removed) As known in the art, such exendin analogs are preferably amidated, but within the contex of the present invention, may c Additional exemplary exendin Serial No. PCT/US98/16387 ptionally be in the acid form unless otherwise specified. analogs and derivatives are described in PCT Applicatioi filed Aug. 6, 1998, entitled "Novel Exendin Agonis Compounds," which claims tie benefit of U.S. patent application Ser. No. 60/055,404 filed Aug. 8, 1997, both of wiich are herein incorporated by reference. Other exendir analogs and derivatives are d filed Nov. 13, 1998, entitled 'Novel Exendin Agonist Compounds," which claims th benefit of U.S. Provisional Application No. 60/065,442 filed Nov. 14, 1997, both o which are herein incorporated by reference. Still other exendin analogs and derivative are described in PCT Applicition Serial No. PCT/US98/24273, filed Nov. 13, 1998 entitled "Novel Exendin Agonist Compounds," which claims the benefit of U.S Provisional Application No. 60/066,029 filed Nov. 14, 1997, both of which are herein incorporated by reference. Still other exendin analogs and derivatives are described ir PCT Application Serial No. P T/US97/14199, filed Aug. 8, 1997, entitled "Methods fo: Regulating Gastrointestinal Activity," which is a continuation-in-part of U.S. paten application Ser. No. 08/694,954 filed Aug. 8, 1996, both of which are hereb) incorporated by reference. S PCT Application Serial No. 11 other exendin analogs and derivatives are described ir PCT/US98/00449, filed Jan. 7, 1998, entitled "Use o Exendins and Agonists Therec f for the Reduction of Food Intake," which claims priorit) to U.S. Provisional Applicati* n No. 60/034,905 filed Jan. 7, 1997, both of which are hereby incorporated by refeience. Yet other exendin analogs and derivatives are described in US 2004/020980: the Treatment and Prevention Al, filed December 19, 2003, entitled "Compositions foi f Neuropathy," which is hereby incorporated by reference Bio-Active Peptide Hormone! Modules As discussed above, the hybri 1 polypeptides of the present invention generally comprise at least two bio-active peptid active peptide hormone modi hormone modules covalently linked together. The bio-es may be: (a) native component peptide hormones, (b analogs or derivatives of na activity, (c) fragments of na ive component peptide hormones that retain hormona ive component peptide hormones that retain hormona activity, (d) fragments of anal )gs or derivatives of native component peptide hormone: that retain hormonal activity, (:) structural motifs of native component peptide hormones that impart a desired chemic il stability, conformational stability, metabolic stability receptor interaction, protease the hybrid polypeptide; or ( component peptide hormones stability, metabolic stability, pharmacokinetic characteristic (f) will collectively be referred nhibition, and/or other pharmacokinetic characteristic to I structural motifs of analogs or derivatives of native that impart a desired chemical stability, conformational receptor interaction, protease inhibition, and/or other o the hybrid polypeptide. The structural motifs of (e) and to herein as "peptidic enhancers". Preferred bio-active peptide h Other preferred bio-active peplkde hormone modules include analogs and derivatives of a component peptide hormone s ected from: amylin, ADM, CT, CGRP, intermedin, CCK, GLP-l(l-37), GLP-l(7-37), GLP-l(7-36), GLP-2, OXM, ein the analog or derivative exhibits at least one hormonal activity of the component peptide hormone. The analog may comprise one or more insertions, deletions, or substitutions of the amino acid sequence of the component peptide hormone, and the deri ative may comprise one or more chemical modifications of an amino acid residue of an analog or component peptide hormone, as described more fully herein and known in the a rt. More specifically, analogs anyand/or known in the art. Partici one hormonal activity useful derivatives may be selected from any described above arly preferred analogs and derivatives that exhibit at least s bio-active peptide hormone modules of the invention (Table Removed) specified. Still other preferred bioacthje peptide hormone modules include fragments of a component peptide hormone selected from: amylin, ADM, CT, CGRP, intermedin, CCK, leptin, PYY(l-36), PYY(3-36)J GLP-1 (1-37), GLP-l(7-37), GLP-l(7-36), GLP-2, OXM, exendin-3, and exendin-4, wherein the fragment exhibits at least one hormonal activity o the component peptide hormore. Yet other preferred bioactive peptide hormone modules include fragments of analogs o derivatives of a component pt ptide hormone selected from: amylin, ADM, CT, CGRP intermedin, CCK, leptin, PYY(l-36), PYY(3-36),GLP-l(l-37), GLP-l(7-37), GLP-1(7 36), GLP-2, OXM, exendin-3, and exendin-4, wherein the fragment exhibits at least one hormonal activity of the component peptide hormone. Again, the analog may compris one or more insertions, delet: ons, or substitutions of the amino acid sequence of tto component peptide hormone, and the derivative may comprise one or more chemica known in the art. modifications of an amino aci 1 residue of an analog or component peptide hormone, as described more fully herein Certain preferred fragments following. However, it shou! analogs and derivatives taken fragments described below, arc hat exhibit at least one hormonal activity include the be understood that combinations of the above-described with fragments known in the art, including the preferred contemplated. Amylin: amylin(l-36), amjylin(l-! amylin (1-16), an , amylin(l-20), amylin(l-18), amylin(l-17), , amylin(l-7) CT: CT(8-32), CT(8-: 7), CT(8-26), CT(8-10), CT(18-26), CT(18-27) AFP-6: AFP-6(18-27) CCK: CCK-8, CCK-5, i :CK-4 Leptin: leptin (22-167), 1 ptin(56-73) PYY: PYY(1-35),PYY PYY(3-36), PYY 1-30), PYY(l-25), PYY(1-15), PYY(l-lO), PYY(2-36), 4-36), PYY(5-36) GLP-1 GLP-1(7-37), GLP-1 (7-36), GLP-1 (7-35) Exendin exendin-4(l-27), |exendin-4(l-28), exendin-4(l-29), exendin-4(l-30) or longer Again, as known in the art, within the context of the pre otherwise specified. Further, of the analogs or derivatives analog fragments may include 4(1-27), 5Ala,14Leu,25Phe-combinations of the disclosed ich peptide compounds may preferably be amidated, bu ent invention, may optionally be in the acid form unles he above preferred fragments may be combined with an discussed herein or known in the art. For example, preferre 5Ala,l4Leu,25Phe-exendin-4(l -28), 14Leu,25Phe-exendin exehdin-4(l-28), l4Leu,25Phe-exendin-4(l-27), or any othe ragments, analogs, and derivatives. Yet other preferred bio-act structural motifs of component thereof) that impart a desire I stability, receptor interactio v characteristic to the hybrid following. Again, it should analogs and derivatives taken contemplated. For example, hormone analogs and deriva contemplated as preferred bio- ve peptide modules include "peptidic enhancer", i.e. peptide hormones (including analogs and derivative chemical stability, conformational stability, metaboli protease inhibition, and/or other pharmacokineti tolypeptide. Exemplary peptidic enhancers include th be understood that combinations of the above-describee ogether with the following bio-active peptide modules are last six amino acid residues of amylin family peptid ves known in the art and/or described above are alsc ctive peptide modules. amylin(32-: amylin(36-; 52), ADM( CT(28-32), 37), CGRP( CGRP(37), 47), intermeidin (45 PYY(25-36 PYY(30-36 PYY(27-35 PYY(32-3S Amylin Family PYY 7), amylin(33-37), amylin(34-37), amylin(35-37), 7), amylin(37), ADM(47-52), ADM(48-52), ADM(49- 0-52), ADM(51-52), ADM(52), CT(27-32), CT(27-32), :T(29-32), CT(30-32), CT(31-32), CT(32), CGRP(32- 3-37), CGRP(34-37), CGRP(35-37), CGRP(36-37), ntermedin (42-47), intermedin (43-47), intermedin (44- -47), intermedin (46-47), intermedin (47) , PYY(26-36), PYY(27-36), PYY(28-36), PYY(29-36), PYY(31-36), PYY(32-36), PYY(25-35), PYY(26-35), PYY(28-35), PYY(29-35), PYY(30-35), PYY(31-35), GLP-1 and 2 29-37); frog GLP-1 (30-37); frog GLP-2(24-31), frog Exendin-4 exendin-4(21-39), exendin-4(32-39), exendin-4(33-39), exendin- 4(34-39), e:;endin-4(35-39), exendin-4(36-39), exendin-4(37-39), exendin-4(; 8-39), exendin-4(39) Peptide Module Selection Con The hybrid polypeptides of t active peptide honnone peptide honnone modules honnone module that exhibits terminal end of the hybrid po] in the event that the hybrid honnone modules, may be Iocs In certain embodiments, it mi module exhibiting the at least bio-active peptide honnone m bio-active peptide honnone m C-terminal end of the hybrid p N-terminal direction at the configurations, the C-terminal for amidation. Specific comp be preferably include amylin hGLP-2. Specific componen necessarily preferred (stated module is easily tolerated) inc 1(7-36), and frog GLP-2. Ho\ the C-terminal end of the in fact may preferably be optio The bio-active peptide hormon in the art. Stable linkages m embodiment, the carboxy of z second module. In another modules. Further, if desired, s to stabilize the linkage. By w iderations, Spacers, and Linking Groups modu] es exhi bits e present invention generally comprise at least two bio-of the invention, wherein at least one of the bio-active at least one hormonal activity. The bio-active peptide he at least one hormonal activity may be located at the N-^peptide, the C-terminal end of the hybrid polypeptide, or jolypeptide comprises more than two bio-active peptide ted in the internal portion of the hybrid polypeptide. y be preferable to locate the bio-active peptide hormone one hormonal activity such that the C-terminal end of the dule is amidated. Amidation of the C-terminal end of the xiule may be accomplished by locating the module at the ptide, or by configuring the module in the C-terminal-to-^-terminal end of the hybrid polypeptide. In both nd of the bio-active peptide honnone module is available nent peptide hormones where C-terminal amidation may amily peptide hormones, CCK, PYY, hGLP-1(7-36) and peptide hormones where C-terminal amidation is not cjtherwise, where elongation at the C-terminal end of the ude exendin-4, exendin-4(l-28), GLP-1(7-37), frog GLP-ever, if these component peptide hormones are located at eptide, they may still be optionally amidated, and ally amidated. modules may be covalently linked in any manner known y be used, or cleavable linkage may be used. In one first module may be directly linked to the amino of a embodiment, linking groups may be used to attached acers or turn inducers known in the art may be employed y of example, where amidation of the C-terminal end of the N-terminally located bio-i may be attached to a second known in the art, such as polyaminoacids, e.g., poly-hi bifunctional linker (see, e.g., alanyl, 8-amino-3,6-dioxaoctat the art. active peptide hormone module is not desired, the module module directly, or using any appropriate linking group an alkyl; PEG; amino acid, e.g., Lys, Glu, p-Ala , poly-arg, poly-lys, poly-ala, Gly-Lys-Arg (GKR) etc. Pierce catalog, Rockford, II); aminocaproyl ("Aca"), p-.oyl, or other cleavable and non-cleavable linker known in Where amidation of the C-hormone module is desired, th any appropriate linking group active peptide hormone modiile configured in the C-terminal-linkage, preferred linking groups acids such as Lys, Cys, and Gl As mentioned above, the hyi further stablize the linkage of turn inducer known in the art include mimic A and mimic B terminal end of N-terminally located bio-active peptide : module may again be attached to a second module using jiown in the art. More specifically, in the event that a bio-exhibiting at least one hormonal activity has been -N-terminal orientation, resulting in an amino to amino include dicarboxylic acids, alkyls, PEGs, and amino may rid polypeptides may also preferably include spacer to the bio-active peptide hormone modules. Any spacer or be used. By way of example, referred p-turn mimetics llustrated below, also Ala-Aib and Ala-Pro dipeptides. hormone modules selected frcm: native peptide hormones, analogs and derivatives of peptide hormones that exhibit at least one hormonal activity, fragments of native peptide hormones that exhibit at leist one hormonal activity, fragments of analogs and Exemplary Combinations and J Exemplary combinations of t polypeptides of the invention pecific Embodiments o-active peptide hormone modules to form the hybrid nclude combinations of two or more bio-active peptide derivatives of peptides hormo enhancers, with the proviso activity. The hybrid polypeptides of hormone modules, wherein hormones. In the context of the hybrid polypeptide may be the component peptide hormo of the component peptide amylin family, CCK, the lept family. In certain embodiments, the h more modules that exhibit a polypeptide may comprise a least one hormonal activity c peptide hormone analog. The hormonal activity. The first additional peptide hormone(s), hormones are different from t may be the same or different fr In other embodiments, the hy more modules that exhibit at peptidic enhancer modules, exhibits a at least one hormone 1 or a fragment of a first peptide be covalently linked to a activity, which is in turn li may be located first peptide hormone may be es that exhibit at least one hormonal activity, and peptidi hat at least one module exhibit at least one hormona t ic invention will include at least two bio-active peptidi each module is comprised from component peptidi present invention, the component peptide hormones o the same or different, with the proviso that at least two o les are different. In a preferred embodiment, at least two homiones are from different peptide hormone families, e.g., the n family, PPF, the proglucagon family, and the exendin brid polypeptides of the invention may comprise two or least one hormonal activity. For instance, the hybrid fr gment of a first peptide hormone or analog that exhibits a valently, linked to a fragment of at least one additional additional fragment(s) may optionally exhibit at least one Kptide hormone may be the same or different from the with the proviso that at least one of the additional peptide ic first peptide hormone, and the first hormonal activity m the optional additional hormonal activity. leist secc nd linked to I between two peptide he polypeptides of the invention may comprise one or one hormonal activity in combination with one or more or instance, a fragment of a first peptide hormone that activity may be covalently linked to a peptidic enhancer, hormone that exhibits at least one hormonal activity may peptide hormone that exhibits at least one hormonal a peptidic enhancer. Alternatively, a peptidic enhancer hormone modules as a stabilizing spacer. Again, the same or different from the second peptide hormone, and the first hormonal activity ma be the same or different from the second hormona activity. In another embodiment, the three, four, or more bio-acti lybrid polypeptides of the invention may comprise two e peptide hormone modules. Exemplary combination include a module with a hormonal activity in combination with one, two, or three peptidi enhancers; two modules wit peptidic enhancers; three mo peptidic enhancer, etc. The component peptide horm a hormonal activity in combination with one or twi ules with a hormonal activity in combination with on nes are preferably selected from amylin, adrenomedullin calcitonin, calcitonin gene related peptide, intermedin, cholecystokinin, leptin peptid YY, glucagon-like peptide-1 , glucagon-like peptide 2, oxyntomodulin, or exendin-4. More particularly, preferred module combinations include those involving combination of exendin, amylin, and P combinations include exend Y as the component peptide hormones. Particula n-4/PYY and PYY/exendin-4 combinations, with and without spacers or linking groups. Other combinations include exendin/amylin anc amylin/exendin combinations combinations include amylin/ spacers or linking groups. In one aspect, preferred mod with and without spacers or linking groups. Yet othe 'YY and PYY/amylin combinations, with and withou le combinations include those involving a first module comprising exendin-4, a fragment of exendin-4 that exhibits at least one hormona activity, an exendin-4 analog c a fragment of an exendin-4 combination with at least on derivative that exhibits at least one hormonal activity, o analog that exhibits at least one hormonal activity ir additional bio-active peptide hormone module. In one s linked to one, two, or three additional bio-active peptide In preferred embodiments, a f rst module comprising an exendin-4 peptide is linked to a second bio-active peptide horn lone module comprising an amylin peptide that exhibits ai least one hormonal activity. Ii to a third bio-active peptide another embodiment, the second module is further linkec hormone module comprising a calcitonin peptide thai exhibits at least one hormonal be further linked to a fourth enhancer selected from amyli located at the C-terminal end may be located at the N-termirJal spacers or linkers such as I io 1m ictivity. In yet another embodiment, the third module may io-active peptide hormone module comprising a peptidi peptides. In one embodiment, the first module may b )f the hybrid polypeptide. Alternatively, the first moduli end of the hybrid polypeptide. In certain embodiments be inserted if desired to link the modules. Preferred exendin-4 peptides l4Leu,25Phe-exendin-4(l-28), peptides that exhibit at least such as amylin(l-17), amylin ( such as pramlintide, 2Ala-i calcitonin peptides that exhibit sCT(8-10), sCT(8-27), and, l4Gln,1U8Arg-sCT, and fragmi amylin(32-37), amy!in(33-37); combinations useful in PCT/US05/[XXXXX], Amyli^i concurrently herewith, which i In one aspect, preferred mod comprising exendin-4, a activity, an exendin-4 analog a fragment of an exendin-4 combination with a peptidic 4, exendin-4(l-27), exendin-4( exendin-4(l-28). Preferred PYY(3I-36). In one embodim hybrid polypeptide and the hybrid polypeptide. Alternativ of the hybrid polypeptide and and connec tion include: exendin-4, exendin-4(l-27), exendin-4(l-28) md 5Ala,14Leu,25Phe-exendin-4(l-28). Preferred amylin hormonal activity include amylin, amylin fragments 1-16), amylin(l-15), and amylin(l-7), and amylin analogs 2>7Ala-h-amylin, and fragments thereof. Preferred at least one hormonal activity sCT, sCT fragments such as calcitonin analogs such as !8Arg-sCT, 14Gln,18Arg-sCT, nts thereof. Preferred amylin peptidic enhancers include and amylin(34-37), and analogs thereof. Amylin/sCT with the present invention inlcude those disclosed in Family Agonist, Attorney Docket 18528.835, filed herein incorporated by reference. frag n or le combinations include those involving a first module ,ent of exendin-4 that exhibits at least one hormonal derivative that exhibits at least one hormonal activity, or analog that exhibits at least one hormonal activity in enjiancer. Preferred exendin-4 compounds include: exendin--28), 14Leu,25Phe-exendin-4(l-28), and 5Ala,14Leu,25Phe- pe|ptidic enhancers include: PYY(25-36), PYY(30-36) and nt, the first module is located at the C-terminal end of the peptidic enhancer is located at the N-terminal end of the ly, the first module may be located at the N-terminal end peptidic enhance may be located at the C-terminal end the of the hybrid polypeptide. In be inserted if desired to attach :ertain embodiments, spacers or linkers such as pAla may he modules. In another aspect, preferred comprising exendin-4, a activity, an exendin-4 analog i a fragment of an exendin-4 combination with a second least one hormonal activity, hormonal activity, or a fragm activity. Again, preferred exendin-4(l-28), l4Leu,25Phe 14Leu-exendin-4(l-28). Prefi 8(Phe(CH2SO3)). In one the hybrid polypeptide and th hybrid polypeptide. Alternativ of the hybrid polypeptide and of the hybrid polypeptide. In be inserted if desired to attach module combinations include those involving a first module fragnent of exendin-4 that exhibits at least one hormonal derivative that exhibits at least one hormonal activity, or analog that exhibits at least one hormonal activity in module comprising CCK, a fragment of CCK that exhibits at i CCK analog or derivative that exhibits at least one «t of a CCK analog that exhibits at least one hormonal ex^ndin-4 compounds include: exendin-4, exendin-4(l-27), ;xendin-4(l-28), 5Ala,14Leu,25Phe-exendin-4(l-28), and rred CCK compounds include: CCK-8, and CCK-embojiiment, the first module is located at the C-terminal end of second module is located at the N-terminal end of the :ly, the first module may be located at the N-terminal end the peptidic enhance may be located at the C-terminal end pertain embodiments, spacers or linkers such as PAla may the modules. In another aspect, preferred comprising amylin, a fragment amylin analog or derivative ths an amylin analog that exhibits second module comprising wi 36). In one embodiment, the polypeptide and the peptidic polypeptide. Alternatively, the hybrid polypeptide and the hybrid polypeptide. In certair inserted if desired to attach the nodules. peptid module combinations include those involving a first module of amylin that exhibits at least one hormonal activity, an t exhibits at least one hormonal activity, or a fragment of at least one hormonal activity in combination with a h a peptidic enhancer, such as PYY(25-36) or PYY(30-module is located at the C-terminal end of the hybrid ^nhancer is located at the N-terminal end of the hybrid first module may be located at the N-terminal end of the idic enhance may be located at the C-terminal end of the embodiments, spacers or linkers such as pAla may be 56 Other preferred module combinations include those involving combinations of exendin and CCK or amylin, calcitcnin, and CCK as a tertiary combination. Particula combinations include exendir/CCK and CCK/exendin, with and without spacers o linkers and linking groups. CCK/amylin/calcitonin/amylin may independently be a peptic on the desired properties of the Yet other preferred module Other combinations include CCK/amylin/calcitonin anc with and without spacers or linking groups. Each module c enhancer or may exhibit a hormonal activity, depending hybrid polypeptide. :ombinations include those involving combinations o: exendin, amylin and calcitonin as tertiary and tetra-hybrid molecules. Exemplary combinations include exen lin/amylin/calcitonin; exendin/amylin/calcitonin/amylin amylin/calcitonin/exendin; and amylin/calcitonin/amylin/exendin combinations, with and without spacers or linking gioups. Each module may independently be a peptidic enhancer or may exhibit a hor nonal activity, depending on the desired properties of the hybrid polypeptide. In one embodiment, when one at least one hormonal activity of the bio-active peptide hormone module(s) that exhibits is amylin or an analog or fragment thereof, and a second bio-active peptide hormone module comprises CCK, then the hybrid polypeptide should preferably comprise a third bic -active peptide hormone module selected from a different component peptide hormone. Exemplary third bio-active peptide hormone modules include calcitonins, more prefe 'ably salmon calcitonin, analogs or fragments thereof. In another embodiment, whei one of the bio-active peptide hormone module(s) that exhibits at least one hormonal activity is amylin or an analog or fragment thereof, and a second bio-active peptide honaone module comprises CT, then the hybrid polypeptide should preferably comprise a different component peptide bird bio-active peptide hormone module selected from a lormone. Exemplary third bio-active peptide hormone modules include exendin-4, analogs or fragments thereof. In yet another embodiment, wi len one of the bio-active peptide hormone module(s) that exhibits at least one hormonal activity is GLP-1 or an analog or fragment thereof, and a second bio-active peptide horn one module is a peptidic enhancer comprising an exendin The hybrid polypeptides of the including, but are not limited sequence of such hybrid polypiptidi the hybrid polypeptides of the essential" amino acid residue, acid residue is a residue that human amino acid sequence fragment, without abolishing ( receptor agonist activity of the Preferred substitutions includ present invention may also comprise further modifications o, substitution, deletion, and insertion to the amino acid ides and any combination thereof. In a preferred aspect, invention include one or more modifications of a "non-In the context of the invention, a "non-essential" amino can be altered, i.e., deleted or substituted, in the native of the fragment, e.g., the component peptide hormone r substantially reducing the component peptide hormone lybrid polypeptide. conserved amino acid substitutions. A "conservative n which the amino acid residue is replaced with an amino (r side chain, or physicochemical characteristics (e.g., isosteric, hydrophobic features). Families of amino acid residues having similar side acids with basic side chains aspartic acid, glutamic acid), glutamine, serine, threonine, alanine, valine, leucine, i chains (e.g., threonine, valin phenylalanine, tryptophan, The present invention also r derivatives include molecules, such as polyethylei (e.g., stearyl, palmitoyl, octan poly-his, poly-arg, poly-lys, also include small molecule branched, cyclic, fused, molecules will preferably hav 20,000 Daltons. chains are known in the art. These families include amino e.g., lysine, arginine, histidine), acidic side chains (e.g. uncharged polar side chains (e.g., glycine, asparagine tirosine, methionine, cysteine), nonpolar side chains (e.g., isoleu;ine, proline, phenylalanine, tryptophan), p-branched side ;, isoleucine) and aromatic side chains (e.g., tyrosine, histidine). iene aid ilates to derivatives of the hybrid polypeptides. Such hybrid pol)jpeptides conjugated to one or more water soluble polymer glycol ("PEG") or fatty acid chains of various lengths >yl, etc.), or by the addition of polyamino acids, such as poly-ala. Modifications to the hybrid polypeptides can substituents, such as short alkyls and constrained alkyls (e.g., adamkntyl), and aromatic groups. The water soluble polymer e a molecular weight ranging from about 500 to about Such polymer-conjugations singularly at the N- or C-sequence of the hybrid derivatization along the hybri The water soluble polymer mo group, and may be linked by '. acid, glutamic acid, or cysteine be linked with diamine and polypeptides of the invention an epsilon amino group on a ly and small molecule substituent modifications may occur termihus or at the side chains of amino acid residues within the polyrjeptides. Alternatively, there may be multiple sites of polypeptide. Substitution of one or more amino acids luiamic acid, or cysteine may provide additional sites for Patent Nos. 5,824,784 and 5,824,778. Preferably, the jugated to one, two, or three polymer molecules. are ecules are preferably lined to an amino, carboxyl, or thiol or C terminus, or at the side chains of lysine, aspartic Alternatively, the water soluble polymer molecules may dicjarboxylic groups. In a preferred embodiment, the hybrid e conjugated to one, two, or three PEG molecules through ine amino acid. Hybrid polypeptide derivatives chemical alterations to one include amidation, glycosyl cyclization. The chemical alt the side chains of amino polypeptides. In one embodirr or -NHj group. In another Examples of the hybrid pol Sequence Listing and Use of Hybrid Polvpeptides in Disorders of the invention also include hybrid polypeptides wit r more amino acid residues. Such chemical alteration ation , acylation, sulfation, phosphorylation, acetylation, an rations may occur singularly at the N- or C-terminus or a cid residues within the sequence of the PPF hybri ent, the C-terminus of these peptides may have a free -OH nbodiment, the N-terminal end may be capped with ar in isopropyloxycarbonyl group, an n-butyloxycarbony p, an isocaproyl group (isocap), an octanyl group, an octy 8-aminooctanic acid group. In a preferred embodiment brmation of disulfide bridges. Alternatively, there may Ix ation along the hybrid polypeptide. further d iscussed peptides of the present invention are provided in th in the Examples section below. he Treatment or Prevention of Metabolic Conditions or In another aspect of the im provided, wherein the rm prophylactically effective amount a preferred embodiment, the s is generally defined as a bod) subject, including those with t reduce body weight is included resistant, glucose intolerant, In other aspects of the inven availability, causing weight Ic content or increasing energy e profile (including reducing LE ention, methods for treating or preventing obesity are hod comprises administering a therapeutically o; of a hybrid polypeptide to a subject in need thereof. Ir bject is an obese or overweight subject. While "obesity' mass index over 30, for purposes of this disclosure, an> body mass index of less than 30, who needs or wishes tc in the scope of "obese." Subjects who are insulir have any form of diabetes mellitus (e.g., type 1, 2 01 from this method. on, methods of reducing food intake, reducing nutrien s, affecting body composition, and altering body energj penditure, treating diabetes mellitus, and improving lipic L cholesterol and triglyceride levels and/or changing HDL cholesterol levels) are providec, an effective amount of a hybri the methods of the invention can be alleviated by reducing administering to said subject a hybrid polypeptide of the i limited to, hypertension, dysli resistance, obesity, and diabete Without intending to be limite i administered hybrid polypepti in the delay of gastric causation of weight loss are de classes in, or similar to, thosereceptor or receptors similar to Additional assays useful to th DIO mice can be implanted deliver either vehicle (50% invention. The pumps of the ug/kg/d of a compound of the i: Body weights and food intak mve ition wherein the methods comprise administering to a subject polypeptide of the invention. In a preferred embodiment, re used to treat or prevent conditions or disorders which nutrient availability in a subject in need thereof, comprising therapeutically or prophylactically effective amount of a Such conditions and disorders include, but are not idemia, cardiovascular disease, eating disorders, insulin-mellitus of any kind. ices empty ng. by theory, it is believed that the effects of peripherally-of the present invention in the reduction of food intake, , in the reduction of nutrient availability, and in the ermined by interactions with one or more unique receptor in the PP family. More particularly, it appears that a the PYY-preferring (or Y7) receptors are involved. con position. obese C57BL/6J Diets contir ue invention include those that can determine the effect of . An exemplary assay can be one that involves (DIO) mouse model for metabolic disease. Prior to the mice can be fed a high-fat diet (#D 12331, 58% of :, Inc.,) for 6 weeks beginning at 4 weeks of age. During to eat their high-fat diet. Water can be provided ad 3ne group of similarly-aged non-obese mice can be fed a calories from fat) for purposes of comparing metabolic 'vith subcutaneous (SC) intrascapular osmotic pumps to dii lethylsulfoxide (DMSO) in water) or a compound of the after group can be set to deliver any amount, e.g., 1000 vention for 7-28 days. can be measured over regular intervals throughout the quotient (RQ, defined as C02 production -r O2 consumption) and metabolic rate can be dete mined using whole-animal indirect calorimetry (Oxymax, Columbus Instruments, Columbus, OH). The mice can be euthanized by isoflurane overdose, and an index of ac iposity (bilateral epididymal fat pad weight) measured. Moreover, prior to determinati mass) for each mouse can b >n of epididymal weight, body composition (lean mass, fat ! analyzed using a Dual Energy X-ray Absorptiometry (DEXA) instrument per manufacturer's instructions (Lunar Piximus, GE Imaging System). In the methods of the those having a potency in on invention, preferred PPF polypeptide of the invention are of the assays described herein (preferably food intake, gastric emptying, pancreatic secretion, weight reduction or body composition assays) which is greater than the poten In addition to the amelioration reduced food intake, weight lo y of a component peptide hormone in that same assay. of hypertension in subjects in need thereof as a result of s, or treating obesity, compounds of the invention may be used to treat hypotension. Compounds of the invention rriay also be useful for potentiating, inducing, enhancing or restoring glucose responsivity n pancreatic islets or cells. These actions may be useful for treating or preventing com iitions associated with metabolic disorders such as those described above and in U.S patent application no. US20040228846. Assays for determining such activity are linown in the art. For example, in published U.S. patent application no. US200402288^6 (incorporated by reference in its entirety), assays are described for islet isolation culture as well as determining fetal islet maturation. In the examples of patent applica ion US20040228846, intestine-derived hormone peptides including pancreatic polypepti PYY, secretin, glucagon-like le (PP), neuropeptide Y (NPY), neuropeptide K (NPK), >eptide-l (GLP-1) and bombesin were purchased from Sigma. Collagenase type XI was obtained from Sigma. RPMI 1640 culture medium and obtained from 6-8 week old lats. Fetal rat islets were obtained as follows. Pregnant female rats were sacrificed on pregnancy day e21. Fetuses were removed from the uterus. fetal bovine serum were obtair. insulin antibody ([125I]-RIA kit Post-partem rat islets were o ed from Gibco. A radioimmunoassay kit containing anti-was purchased from Linco, St Louis. tained from P-02 year old rats. Adult rat islets were 10-14 pancreata were dissecte 1 pancreas were pooled, sus; incubated at 37° C for 8-10 m adding 10 volumes of ice-cole The islets were then purified (FBS)/RPMI medium with or 20 islets were hand picked into islets were first washed with containing 3 mM (low) gluco collecting the supernatant, the one hour at 37° C. The i assayed by radioimmunoassa cultured for 5 days in the GLP-1 orBombesin. pen Jed msu .in pre: ence from each litter and washed twice in Hanks buffer. Th in 6 ml 1 mg/ml collagenase (Type XI, Sigma) am lutes with constant shaking. The digestion was stopped b) Hanks buffer followed by three washes with Hanks buffer y Ficoll gradient and cultured in 10% fetal bovine serum without addition of 1 uM IBMX. At the end of five days each tube and assayed for static insulin release. Generally CRP buffer and then incubated with 1 ml of KRP buffe * for 30 minutes at 37° C. with constant shaking. Afte islets were then incubated with 17 mM (high) glucose fo released from low or high glucose stimulation were (RIA) using the [125I]-RIA kit. E21 fetal islets were of 200 ng/ml PYY, PP, CCK, NPK, NPY, Secretin An exemplary in vivo assays is rat, an inbred (>F30 Generatic ns) fa/fa males fed a standard begins to develop at about se 500 mg/DL by 10 to 11 development of diabetes. How lean control litter mates, higher than those of leans. In per group, received the infusj on control, 2) and 3), PYY with respectively. Four measurements day 7 and day 14: 1) plasmi triglycerides (TG) level, as these assays can be used with Other uses contemplated for aluminum (Al) concentrations is also rodent Trig lyceride tie com provided using the Zucker Diabetic Fatty (ZDF) male rat model that spontaneously expresses diabetes in al diet Purina 5008. In ZDF fa-fa males, hyperglycemia en weeks of age and glucose levels (fed) typically reach eeks of age. Insulin levels (fed) are high during the ver, by 19 weeks of age insulin drops to about the level of and cholesterol levels of obese rats are normally assay, three groups of 7-week old ZDF rats, with 6 rats treatment by ALZA pump for 14 days: 1) vehicle two different doses, 100 pmol/kg/hr and 500 pmol/kg/hi ts were taken before the infusion and after the infusion at glucose level, 2) plasma insulin level, and 3) plasma ell as oral glucose tolerance (OGTT) test. Accordingly, pounds of the invention to test for desired activity. the hybrid polypeptides include methods for reducing in the central nervous system (see U.S. Pat. 6,734,166, incorporated by reference in Alzheimer's disease. Assays be found in US Pat 6,734,166 housed in Nalgene® brand m adjust to the cages before Rat and Moust/Auto 6F5K52, the 16 hours prior to euthan subcutaneous injections of eithler end of day 13 for one Mice brain samples were we microwave digestion in low tr for Al content using Inducti Annals of Clinical and Labor during analysis took place in systems to minimize background The compounds of the inven related to their antisecretory gastrointestinal secretions by inhibiting secretion of hormon Anti-secretory properties incl can be useful in the treatment pancreatitis, Barrett's esophagi Compounds of the invention a disorders (see e.g., Harrison's York, 12th Ed.) that are assoc as well as decreased absorpti bowel syndrome, or the diarrl e.g., ileostomy. Examples of diarrhea, acute bacterial diarrhjea to protozoal infections), or expe imentation. s entirety) for treating, preventing, or delay the onset o )r determining effects on Al are known in the art and car using diploid and Ts mice. These mice were individuall tabolism or polypropylene cages and given three days t . Mice had free access to food (LabDiet® NIH t. Louis, Mo.) and water during the experiment except fo ia when no food was provided. Mice were given dail experii aent active compound or saline. Mice were sacrificed at th and day 3 for another, and samples were collectec jhted in clean teflon liners and prepared for analysis b; ce element grade nitric acid. Sample were then analyzed ely Coupled Plasma Mass Spectrometry (Nuttall et al tory Science 25, 3, 264-271 (1995)). All tissue handling a clean room environment utilizing HEPA air filtration contamination. aid on exhibit a broad range of biological activities, som s or neurotransmitters which stimulate intestinal secretion de inhibition of gastric and/or pancreatic secretions and r prevention of diseases and disorders including gastritis s, and Gastroesophageal Reflux Disease. •e useful in the treatment of any number of gastrointestina rinciples of Internal Medicine, McGraw-Hill Inco, Nevated with excess intestinal electrolyte and water secretior n, e.g., infectious diarrhea, inflammatory diarrhea, shor ea which typically occurs following surgical procedures nfectious diarrhea include, without limitation, acute vira (e.g., salmonella, campy lobacter, and clostridium or due traveller's diarrhea (e.g., Norwalk virus or rotavirus) Examples of inflammatory di tropical sprue, chronic syndrome. It has also been d treat an emergency or life-thre after surgery or due to cholera. Compounds of the invention damage as opposed to merely damage (for example, diarrhea) ulcerative colitis, inflammatory loss of bowel mucosal functio: its entirety). Assays for such i old male HSD rats, ranging : allowed ad libitum access to a water. The animals were reproducible rat model of chromic Morris GP, et al., "Hapten- i rat colon." Gastroenterology. inflammation and ulceration, ; colonic inflammatory disease treatments potentially applicab Rats were anesthetized with 3' 37°C. A gavage needle waj trinitrobenzenesulfonic acid the lumen of the colon through of 0 0.4-0.6 mL, as described i groups received saline solution Four days after induction were then euthanized by diarrhea include, without limitation, malabsorption syndrome pancreatitis, Crohn's disease, diarrhea, and irritable bowel icovered that the peptides of the invention can be used to itening situation involving a gastrointestinal disorder, e.g. fasted may also be useful for treating or preventing intestinal treating the symptoms associated with the intestinal Such damage to the intestine may be, or a result of, bowel disease, bowel atrophy, loss bowel mucosa, and/or (see WO 03/105763, incorporated herein by reference in ctivity, as described in WO 03/105763, include 11 week 50- 300 grams housed in a 12:12 light:dark cycle, and standard rodent diet (Teklad LM 485, Madison, WI) and for 24 hours before the experiment. A simple and ic colonic inflammation has been previously described by induced model of chronic inflammation and ulceration in the 1989; 96:795-803. It exhibits a relatively long duration of ffording an opportunity to study the pathophysiology of n a specifically controlled fashion, and to evaluate new e to inflammatory bowel disease in humans. .11 isofluorane and placed on a regulated heating pad set at inserted rectally into the colon 7 cm. The hapten (TfNBS) dissolved in 50% ethanol (v/v) was delivered into the gavage needle at a dose of 30 mg/kg, in a total volume Mazelin, et al.,Juton Nerv Syst. 1998;73:38 45. Control (NaCl 0.9%) intracolonically. of colitis, itis, the colon was resected from anesthetized rats, which decapitation. Weights of excised colon and spleen were measured, and the colons pi Inflammation was defined as regions > Hybrid polypeptides of the invention tumors (e.g., inhibit the prolii ;ration include reducing the proliferat on cells which may be treated in adenomas, microcystic tumors reducing the proliferation of malignant from the ducts, acini, or islet reference in its entirety) provide properties. For example, the ' human pancreatic adenocarcinjoma from suppliers such as Americ; in two tumor cells were grown ir bovine serum, 29.2 mg/L of gl and fungizone solution (JRH NAPCO water jacketed 5 % trypsin (Clonetics, San Diego, of tumor cells was achieved, centrifuge at 4 degrees Celcii^s, culture media. Viable cells wen Ten thousand, 20,000, 40,000 microculture plates (Costar, media per well. Cells were all or test peptide. Fresh culture incubation of pancreatic tumor 6 hours and 36 hours in length and 2.5 pmol per well (N =14' 400 pmol, 40 pmol, and 4 pmc mimic the volume and physical otographed for scoring of gross morphologic damage, of hyperemia and bowel wall thickening. C02 Cells may also be used to treat or prevent pancreatic of pancreatic tumors). Methods of the invention of tumor cells. The types of benign pancreatic tumor iccordance with the present invention include serous cyst and solid-cystic tumors. The method is also effective in pancreatic tumor cells such as carcinomas arising of the pancreas. U.S. Pat. 5,574,010 (incorporated by s exemplary assays for testing anti-proliferative )10 patent provides that PANC-1 and MiaPaCa-2 are two cancer cell lines which are available commercially Type Culture Collection, ATCC (Rockville, Md.). The RPMI-1640 culture media supplemented with 10% fetal atamine, 25 ug gentamicin, 5 ml penicillin, streptomycin, Biosciences, Lenexa, Kans.) at 37 degrees Celcius in a incubator. All cell lines were detached with 0.25 % alif.) once to twice a week when a confluent monolayer were pelleted for 7 minutes at 500 g in a refrigerated s, and resuspended in trypsin free fortified RPMI 1640 counted on a hemocytometer slide with trypan blue. media and 80,000 cells of each type were added to 96 well mbridge, Mass.) in a total volume of 200 ul of culture wed to adhere for 24 hours prior to addition of the PYY edia was exchanged prior to addition of peptides. In vitro ells with either PYY or test compound was continued for PYY was added to cells at doses of 250 pmol, 25 pmol, Test compound was added to cells cultures at doses of per well. Control wells received 2 ul of 0.9% saline to disturbance upon adhered tumor cells. Each 96 well plate contained 18 control wells experimentation. Ninety-six concentrations of PYY and test At the end of the diphenyltetrazolium Bromide, added to fresh culture media at to allow for comparison within each plate durin (96) well plates were repeated 6 times with varyin compound in both the PANC-1 and MiaPaCa-2 cells. ncubation period, 3-(4,5-dimethylthiazolyl-2-yl)-2,5 MTr tetrazolium bromide (Sigma, St. Louis, Mo.) wa 0.5 mg/ml. Culture media was exchanged and tumor cell were incubated for 4 hours vdth MTT tetrazolium bromide at 37°C. At the end o ELISA reader (Molecular Devices, Menlo Park, Calif.). The MTT assay measure mitochondria! NADH depende tit dehydrogenase activity, and it has been among the mos incubation, culture media was 200 ul of dimethyl sulfoxic formazon was performed by o aspirated. Formazon crystal precipitates were dissolved in (Sigma, St. Louis, Mo.). Quantitation of solubilized )taining absorption readings at SOO run wavelength on an sensitive and reliable method cells. (Alley, M. C., et al, Ca to quantitative in vitro chemotherapy responses of tumo cer Res., 48:589-601, 1988; Carmichael, J., et al, Cance, Res., 47:936-942, 1987; McFale, A. P., et al, Cancer Lett., 41:315-321, 1988; and Saxton, R. E., et al, J. Clin. absorption readings at 550 r conditions and verifying diffe aser Med. and Surg., 10(5):331-336, 1992.) Analysis o m were analyzed by grouping wells of the same tes ences occurring between control and the various peptide concentration treatments by one-way ANOVA. An exemplary in vivo assay is also provided. The human pancreatic ducta adenocarcinoma Mia Paca-2 v and test compound. Sevent orthotopically transplanted inti treated with either PYY or tes as examined for in vivo growth inhibition by peptide YY thousand to 100,000 human Mia PaCa-2 cells were 48 male athymic mice. After one week, the animals were compound at 200 pmol/kg/hr via mini-osmotic pumps foi four weeks. The paired cultui es received saline. At sacrifice, both tumor size and mass were measured. Control mice as evidenced by histologic se lad significant human cancer growth within the pancreas ions. At 9 weeks, ninety percent (90%) of control mic« had substantial metastatic disease. Tumor mass was decreased by 60.5 % in test treatec mice and 27% in PYY treated mice. For all indications, in preferre)! administered peripherally at a divided doses or controlled per dose, more preferably about 50 ug/kg. Dosages in derivative, of course, and may In the methods of the presen administered separately or tog that exhibit a long term or not limited to other compounds analog agonist, salmon calcito protein) or leptin agonist, an analog agonist. Suitable amylin (also known as "pran 5,998,367). The CCK used i in, for example, (Pelleymount 269: 543-6 (1995); Campfiel include exendin-3 and exendiii-4 those described in PCX Public about embodiments, the hybrid polypeptide of the invention i dose of about 0.5 ng to about 5 mg per day in single o continual release, or at about 0.01 ug/kg to about 500 ug/k 0.05 ug/kg to about 250 ug/kg, most preferably belov hese ranges will vary with the potency of each analog o be determined by one of skill in the art. invention, hybrid polypeptides of the invention may be ther with one or more other compounds and composition -term action to reduce nutrient availability, including, bu and compositions that comprise an amylin or amylir lin, a cholecystokinin (CCK) or CCK agonist, a leptin (OB xendin or exendin analog agonist, or a GLP-1 or GLP-aniylin agonists include, for example, [25>28t29Pro-] human intide," and described in U.S. Pat. Nos. 5,686,511 anc is [preferably CCK octapeptide (CCK-8). Leptin is discussec r et al., Science 269: 540-3 (1995); Halaas et al., Science et al., Science 269: 546-9 (1995)). Suitable exendins , and exendin agonist compounds include, for example ions WO 99/07404, WO 99/25727, and WO 99/25728. Polypeptide Production and Pi rification The hybrid polypeptides desc techniques or chemical peptu automated or semi-automated The hybrid polypeptides of tf support in accordance with co commercially available and c£ Stewart and Young, Solid Pha Tarn et al, J. Am. Chem. Soc. and Barany and Merrifield, Tl bed herein may be prepared using standard recombinani e synthesis techniques known in the art, e.g., using ar >eptide synthesizer, or both. e invention can be synthesized in solution or on a solid ventional techniques. Various automatic synthesizers are be used in accordance with known protocols. See, e.g. e Peptide Synthesis, 2d. ed., Pierce Chemical Co. (1984); 105: 6442 (1983); Merrifield, Science 232: 341-7 (1986); e Peptides, Gross and Meienhofer, eds., Academic Press, New York, 1-284 (1979). automatic peptide synthesizer California) using the NMP/H Applied Biosystems User's July 1, 1988, section 6, pp. 49 capping. Peptides may also (Model MPS 350, Louisvill (preparative and analytical) us C18 preparative column (10 peptide can be readily synth* identify reactive peptides. lid phase peptide synthesis may be carried out with ar e.g., Model 430A, Applied Biosystems Inc., Foster City •Bt (Option 1) system and tBoc or Fmoc chemistry (see Manual for the ABI 430A Peptide Synthesizer, Version 1.3B 70, Applied Biosystems, Inc., Foster City, California) witr e assembled using an Advanced Chem Tech Synthesize Kentucky). Peptides may be purified by RP-HPLC ig, e.g., a Waters Delta Prep 3000 system and a C4, C8, o , 2.2x25 cm; Vydac, Hesperia, California). The activi ized and then screened in screening assays designed to The hybrid polypeptides of recombinant techniques well Cloning: A Laboratory Man polypeptides produced by polynucleotide. One skilled i DNA and RNA, that encode s be obtained from the wild-type usage, or may be engineered incorporate codons facilitating Such manufacturing sequence; known in the art. See, e.g. optionally encode an N-termi al the present invention may be containing amino acids and methods known in the art. (1986). ic present invention may alternatively be produced bj cnown in the art. See, e.g., Sambrook et al., Molecula* al, 2d ed, Cold Spring Harbor (1989). These hybrid ecombinant technologies may be expressed from a the art will appreciate that the polynucleotides, including ch the various fragments of the hybrid polypeptides ma; cDNA, taking into consideration the degeneracy of codon as desired. These polynucleotide sequences may transcription and translation of mRNA in microbial hosts may readily be constructed according to the methods wel WO 83/04053. The polynucleotides above may also pe ptidi methionyl residue. Non-peptide compounds useful in epared by art-known methods. For example, phosphate-ides containing such amino acids may be prepared using e, e.g., Bartlett and Landen, Bioorg. Chem. 14: 356-77 A variety of expression vectc hybrid polypeptide coding microorganisms such as bactet host systems may be utilized to contain and express i equence. These include but are not limited tc transformed with recombinant bacteriophage, plasmid 01 cosmid DNA expression vectors cell systems infected with viru transfected with virus express mosaic virus, TMV) or plasmid); or animal cell systenjs productions include but are ovary (CHO) cell lines, COS MDCK, A549, PC 12, K562 expression of the protein are As such, polynucleotide sequ new and useful viral and transfected procaryotic and mammalian cells grown in such host cells capable of polynucleotide sequences therapy in instances where un not ; yeast transformed with yeast expression vectors; insec > expression vectors (e.g., baculovirus); plant cell system >n vectors (e.g., cauliflower mosaic virus, CaMV; tobacco transformed with bacterial expression vectors (e.g., Ti or pBR322 . Mammalian cells that are useful in recombinant protein limited to VERO cells, HeLa cells, Chinese hamstei cells (such as COS-7), WI 38, BHK, HepG2, 3T3, RIN 293 cells. Exemplary protocols for the recombinan d scribed herein below. nces provided by the invention are useful in generating pljasmid DNA vectors, new and useful transformed anc eucaryotic host cells (including bacterial, yeast, and cullture), and new and useful methods for cultured growth of expression of the present hybrid polypeptides. The encoding hybrid polypeptides herein may be useful for geneproduction of the component peptide hormone(s) of the the need for increased levels of such would be met. The present invention also pro present hybrid polypeptides. from a host cell containing mi (a) culturing said host cell containing under conditions facilitating t such hybrid polypeptides. Host cells may be prokaryotic as Chinese Hamster Ovary (CIjIO) cells or other cells), yeast cells. Mammalian host systems for known to those of skill in the to process the expressed protim ides for processes for recombinant DNA production of the Pjrovided is a process for producing the hybrid polypeptides :eic acids encoding such hybrid polypeptides comprising: polynucleotides encoding such hybrid polypeptides e expression of such DNA molecule; and (b) obtainingeukaryotic and include bacteria, mammalian cells (such cells, monkey cells, baby hamster kidney cells, cancer and insect cells. irt he expression of the recombinant protein also are well . Host cell strains may be chosen for a particular ability or produce certain post-translation modifications that will be useful in providing pWein activity. Such modifications of the polypeptid include, but are not limited to, lipidation and acylation. Po icetylation, carboxylation, glycosylation, phosphorylation xanslational processing, which cleaves a "prepro" form o the protein, may also be important for correct insertion, folding and/or function Different host cells, such as CHO, HeLa, MDCK, 293, WI38, and the like, have specif! cellular machinery and characteristic mechanisms for such post-translational activities and may be chosen to ensure lie correct modification and processing of the introducec foreign protein. Alternatively, a yeast system njay be employed to generate the hybrid polypeptides of th present invention. The codin ion using one primer containing nucleotides 1-20 of the mother primer complementary to nucleotides 255-235 o: ; region of the hybrid polypeptide cDNA is amplified by PCR. A DNA encoding the yeast pre-pro-alpha leader sequence is amplified from yeas genomic DNA in a PCR reac alpha mating factor gene and this gene (Kurjan and Hersko vitz, Cell, 30: 933-43 (1982)). The pre-pro-alpha leader coding sequence and hybrid f olypeptide coding sequence fragments are ligated into a plasmid containing the yeast alcohol dehydrogenase (ADH2) promoter, such that the promoter directs expression of a fusion protein consisting of the pre-pro-alpha factor fused to the mature hybrid pol i/peptide. As taught by Rose and Broach, Meth. Enz. 185 234-79, Goeddel ed, Acadenic Press, Inc., San Diego, California (1990), the vector further includes an ADH2 tra iscription terminator downstream of the cloning site, the yeast "2-micron" replication genes, the E. coli (3-lactamase and leu-2d genes provide for rigin, the yeast leu-2d gene, the yeast REP1 and REP2 ;ene, and an E. coli origin of replication. The p-lactamase selection in bacteria and yeast, respectively. The leu-2d gene also facilitates increasec copy number of the plasmid in yeast to induce higher levels of expression. The REI1 and REP2 genes encode proteins involved in regulation of the plasmid copy number. The DNA construct described using a known method, e.g., 280-97 (1990)). The ADH2 in the preceding paragraph is transformed into yeast cells ithium acetate treatment (Steams et al, Meth. Enz. 185: promoter is induced upon exhaustion of glucose in the growth media (Price et al., G('ne 55: 287 (1987)). The pre-pro-alpha sequence effects secretion of the fusion prote: cleaves the pre-pro sequence Proc. Natl. Acad. Sci. USA 81 from the cells. Concomitantly, the yeast KEX2 protei from the mature PYY analog polypeptides (Bitter et al 5330-4(1984)). Hybrid polypeptides of the in a commercially available (Invitrogen, San Diego, Cal system also relies on the pre-the insert is driven by the alco The secreted hybrid polypept jle methods used to purify h supernatants. Alternatively, the cDNA e baculovirus expression vecto hybrid polypeptide-containin directions (PharMingen) to in and to produce recombinant media using a heparin-Sephi sequential molecular sizing co in PBS. SDS-PAGE analysis and Edman sequencing on a sequence. For example, the DNA seque plasmid containing a desired p et al., Science 240: 1041-3(1 automated sequencing. The using standard procedures em bacteria (Sambrook et al., suj. supplemented with carbenicil growth in a suitable medium. ;ntion may also be recombinantly expressed in yeast usin pression system, e.g., the Pichia Expression Syste brnia), following the manufacturer's instructions. Thi ro-alpha sequence to direct secretion, but transcription o iol oxidase (AOX1) promoter upon induction by methane is purified from the yeast growth medium by, e.g., th Hid polypeptide from bacterial and mammalian eel coding hybrid polypeptides may be cloned into the pVL1393 (PharMingen, San Diego, California). Thi vector is then used according to the manufacturer' ect Spodoptera frugiperda cells in sF9 protein-free medi •otein. The protein is purified and concentrated from tin rose column (Pharmacia, Piscataway, New Jersey) and umns (Amicon, Beverly, Massachusetts), and resuspended shows a single band and confirms the size of the protein Proton 2090 Peptide Sequencer confirms its N-termina ce encoding the hybrid polypeptide may be cloned into e omoter and, optionally, a leader sequence (see, e.g., Bettei 88)). The sequence of this construct may be confirmed b> asmid is then transformed into E. coli, strain MCI061 toying CaC12 incubation and heat shock treatment of the ra). The transformed bacteria are grown in LB medium n, and production of the expressed protein is induced bj f present, the leader sequence will affect secretion of th( hybrid polypeptide and be cle purified from the bacterial cul Alternatively, the hybrid pol> system. Insect systems for pr In one such system, Autograp a as a vector to express foreign larvae. The hybrid polypepti the virus, such as the polyh promoter. Successful insertiojn inactive and produce recomb viruses are then used to infect polypeptide is expressed (Sm Natl. Acad. Sci. USA 91: 3224 In another example, the DI amplified by PCR and clon (Pharmacia, Piscataway, New protein comprising glutathione -S encoded by a DNA fragment i PCR may be generated to it recombinant fusion protein m protein. The pGEX-3X/PYY XL-1 Blue cells (Stratagene, isolated and grown at 37°C in density at wavelength 600 run presence of 0.5 mM Isoprop Louis, Missouri). Plasmid Dl sequenced using an automate hybrid polypeptide-encoding ved during secretion. The secreted recombinant protein i ire media by the method described herein below. >eptides of the invention may be expressed in an insec tein expression are well known to those of skill in the art californica nuclear polyhedrosis virus (AcNPV) is us& genes in Spodoptera frugiperda cells or in Trichoplusi : coding sequence is cloned into a nonessential region o drin gene, and placed under control of the polyhedrin of hybrid polypeptide will render the polyhedrin gene nant virus lacking coat protein coat. The recombinan S. frugiperda cells or Trichoplusia larvae in which hybrid h et al, J. Virol. 46: 584 (1983); Engelhard et al., Proc (1994)). A sequence encoding the hybrid polypeptide may b d into an appropriate vector, for example, pGEX-3X ersey). The pGEX vector is designed to produce a fusion -transferase (GST), encoded by the vector, and a protein iserted into the vector's cloning site. The primers for the elude, for example, an appropriate cleavage site. The y then be cleaved from the GST portion of the fusion analog polypeptide construct is transformed into E. col La Jolla, California), and individual transformants are B medium (supplemented with carbenicillin) to an optica of 0.4, followed by further incubation for 4 hours in the p-D-Thiogalactopyranoside (Sigma Chemical Co., St A from individual transformants is purified and partially sequencer to confirm the presence of the desired PPF insert in the proper orientation. gsne The fusion protein, expectec bacteria, may be purified as 0.15 MNaCl, lOmMTris, p (Sigma Chemical Co.) for 1 sonication, and cell debris is fusion protein-containing pell layered over 50% glycerol, resuspended in standard phosp The fusion protein is furthe denaturing SDS polyacrylamii K.C1 to visualize the protein, lacking SDS. IftheGST/PY\ as a soluble protein, it may tx Biotech). to be produced as an insoluble inclusion body in th Hows. Cells are harvested by centrifugation; washed i: 8, 1 mM EDTA; and treated with 0.1 mg/mL lysozym min. at room temperature. The lysate is cleared b; jelleted by centrifugation for 10 min. at 12,000xg. Th is resuspended in 50 mM Tris, pH 8, and 10 mM EDTA nd centrifuged for 30 min. at 6000xg. The pellet i ate buffered saline solution (PBS) free of Mg^ and Ca*4 purified by fractionating the resuspended pellet in a gel (Sambrook et al., supra). The gel is soaked in 0.4 Iv which is excised and electroeluted in gel-running buffe analog polypeptide fusion protein is produced in bacteria purified using the GST Purification Module (Pharmacia The fusion protein may be sub polypeptide. The digestion thrombin (4000 U/mg (Sign-temperature and loaded on a products. The gel is soaked in the protein band corresponding polypeptide may be confirmed automated sequencer (Applied In a particularly preferred met of the present invention, 293 hybrid polypeptide cDNA in sequence) and pSV2neo (cont method. Preferably, the vectors Similarly, an alternative construct incorporated can be used. Stat dilution in growth media conte ected to digestion to cleave the GST from the PPF hybrid eaction (20-40 ug fusion protein, 20-30 units human ) in 0.5 mL PBS) is incubated 16-48 hrs. at room denaturing SDS-PAGE gel to fractionate the reaction ).4 M K.C1 to visualize the protein bands. The identity o: to the expected molecular weight of the hybrid by partial amino acid sequence analysis using an iosystems Model 473A, Foster City, California). od of recombinant expression of the hybrid polypeptides ells may be co-transfected with plasmids containing the he pCMV vector (5' CMV promoter, 3' HGH poly A ning the neo resistance gene) by the calcium phosphate should be linearized with Seal prior to transfection using a similar pCMV vector with the neo gene ceil lines are selected from single cell clones by limiting .ning 0.5 mg/mL G418 (neomycin-like antibiotic) for 10- 14 days. Cell lines are blot, and high-expressing cell It is preferable that the production and as such stabl with vectors that contain sele the cells may be allowed to switched to selective media, selection, and its presence all the introduced sequences, proliferated using tissue cultur A number of selection transformed for recombinant p not limited to, HSV thymidin and adenine phosphoribosyltr Also, anti-metabolite resistanc resistance to methotrexate; confers resistance to the chlorsulfuron; and hygro, tha genes that may be useful inc tryptophan, or hisD, which al that give a visual indication f glucuronidase and its substrate Many of the hybrid polypep combination of both automa example, a hybrid polypeptid modifications including delet hybrid polypeptide may be polypeptide containing the m combination thereof, may be screeru d for hybrid polypeptide expression by ELISA or Western nes are expanded for large scale growth. transformed cells are used for long-term, high-yield protei expression is desirable. Once such cells are transforme table markers along with the desired expression cassette jrow for 1-2 days in an enriched media before they ar Fhe selectable marker is designed to confer resistance t ws growth and recovery of cells that successfully expres Resistant clumps of stably transformed cells can be techniques appropriate to the cell. systems ail may be used to recover the cells that have been otein production. Such selection systems include, but ar kinase, hypoxanthine-guanine phosphoribosyltransferase nsferase genes, in tk-, hgprt- or aprt- cells, respectively can be used as the basis of selection for dhfr, that confers that confers resistance to mycophenolic acid; neo, tha inoglycoside, G418; also, that confers resistance to confers resistance to hygromycin. Additional selectabh de trpB, which allows cells to utilize indole in place o ws cells to utilize histinol in place of histidine. Markers r identification of transformants include anthocyanins, GUS, and luciferase and its substrate, luciferin. des of the present invention may be produced using a d peptide synthesis and recombinant techniques. Foi of the present invention may contain a combination o: on, substitution, and insertion by PEGylation. Such a reduced in stages. In the first stage, an intermediate xttfications of deletion, substitution, insertion, and any reduced by recombinant techniques as described. Then after an optional purification PEGylated through chemical from Nectar Transforming hybrid polypeptide. One sk procedure may be generalizec of modifications selected means of modification well kn from itep as described below, the intermediate polypeptide i edification with an appropriate PEGylating reagent (e.g Therapeutics, San Carlos, California) to yield the desire led in the art will appreciate that the above-describe o apply to a hybrid polypeptide containing a combinatio deletion, substitution, insertion, derivation, and othe wn in the art and contemplated by the present invention. It may be desirable to purify Peptide purification techniqu techniques involve, at one polypeptide and non-polypepti|di proteins, the polypeptide of i: electrophoretic techniques to homogeneity). Analytical met are ion-exchange electrophoresis, and isoelectr peptides is reverse phase HP liquid chromatography/mass Desorption lonization (MALD obtained by determining amin Certain aspects of the prese embodiments, the substantial "purified peptide" as used other components, wherein th obtainable state. A purified environment in which it may Generally, "purified" will rel fractionation to remove varioi retains its expressed biologica chromatog raphy e hybrid polypeptides generated by the present invention s are well known to those of skill in the art. Thesi vel, the crude fractionation of the cellular milieu t focusing. A particularly efficient method of purifying C, followed by characterization of purified product b> spectrometry (LC/MS) and Matrix-Assisted Lase ) mass spectrometry. Additional confirmation of purity is acid analysis. heiein t invention concern the purification, and in particulai verification, of an encoded protein or peptide. The term , is intended to refer to a composition, isolatable from peptide is purified to any degree relative to its naturall) >eptide therefore also refers to a peptide, free from th« turally occur. r to a peptide composition that has been subjected tc other components, and which composition substantiallj activity. Where the term "substantially purified" is used. this designation will refer component of the compositio n about 80%, about 90%, about a composition in which the peptide forms the majo such as constituting about 50%, about 60%, about 70% 5% or more of the peptides in the composition. Various techniques suitable fo skill in the art. These include, antibodies, and the like; heat steps such as ion exchange, chromatography; isoelectric fo other techniques. As is gen conducting the various purific omitted, and still result in a protein or peptide. There is no general requirem purified state. Indeed, it is c have utility in certain embodiments fewer purification steps in c general purification scheme, column chromatography performed, a greater "-fold" purificatio chromatography system. Meti have advantages in total recov expressed protein. One may optionally purify an use in peptide purification will be well known to those o "or example, precipitation with ammonium sulphate, PEG lenaturation, followed by centrifugation; chromatographj el filtration, reverse phase, hydroxylapatite and affinity using; gel electrophoresis; and combinations of such and rally known in the art, it is believed that the order o tion steps may be changed, or that certain steps may be suitable method for the preparation of a substantially purified nt that the peptides always be provided in their most ntemplated that less substantially purified products wil Partial purification may be accomplished by using mbination, or by utilizing different forms of the same For example, it is appreciated that a cation-exchange , utilizing an HPLC apparatus, will generally result in than the same technique utilizing a low pressure >ds exhibiting a lower degree of relative purification may ry of protein product, or in maintaining the activity of an isolate such hybrid polypeptides from other components for purifying a polypeptide can be found in U.S. Patent its describe specific exemplary methods for the isolation compositions that may be useful in isolating and purifying the nt invention. Given the disclosure of these patents, it is ic art would be well aware of numerous purification urify hybrid polypeptides from a given source. Also it is contemplated tha chromatography may be emp of the present invention. Pharmaceutical Compositions a combination of anion exchange and immunoattmity yed to produce purified hybrid polypeptide compositions The present invention also therapeutically or prophylactl the invention, or a pharmaceutically acceptable and/or carriers useful in the de include diluents of various ionic strength; additives such Polysorbate 80), anti-oxidants (e.g., thimersol, benzyl alco incorporation of the material i as polylactic acid, polyglyco compositions will influence th in vivo clearance of the Pharmaceutical Sciences 1435 (1990). In general, the present hybri individual component properties. One preferred use the treatment or prevention o compounds of the invention reduce of food intake, and eff relates to pharmaceutical compositions comprising a illy effective amount of at least one hybrid polypeptide of pharmaceutically acceptable salt thereof, together with luents, preservatives, solubilizers, emulsifiers, adjuvants ivery of the hybrid polypeptides. Such compositions may b ffer content (e.g., Tris-HCl, acetate, phosphate), pH andi as detergents and solubilizing agents (e.g., Tween 80, (e.g., ascorbic acid, sodium metabisulfite), preservatives lol), and bulking substances (e.g., lactose, mannitol); i to particulate preparations of polymeric compounds, such ic acid, etc., or in association with liposomes. Such physical state, stability, rate of in vivo release, and rate of resent hybrid polypeptides. See, e.g., Remington's 712, 18th ed, Mack Publishing Co., Easton, Pennsylvania polypeptides will be useful in the same way that the polypeptides are useful in view of their pharmacological s to peripherally administer such hybrid polypeptides for metabolic conditions and disorders. In particular, the ossess activity as agents to reduce nutrient availability, t weight loss. In another embodiment, a preferred use is rpeptides for the treatment of diabetes or diabetes related The present hybrid polypeptidi including formulation for es may be formulated for peripheral administration, ion, oral administration, nasal administration, pulmonary administration, topical admim the art will recognize, compositions according to the the target tissue is available pharmaceutical compositions peripheral method, e.g., by intraperitoneal, intrathecal, sublingual, nasal, anal, vagina particular site. The treatment period of time. Controlled co is also contemplated. The formulation may be liqui Aqueous compositions of the hybrid polypeptide, dissolved aqueous medium. The phrase to molecular entities and untoward reactions when "pharmaceutically acceptable coatings, antibacterial and anti the like. The use of such med; known in the art. Except insofar the active ingredient, its use in active ingredients also can be be convenient to provide a hy reducing, diabetes treating, pi as an amylin, an amylin agoi agonist, or an exendin or administration together. In ot additional agent separately fro: tration, or other types of administration as one skilled in >re particularly, administration of the pharmaceutical >resent invention may be via any common route so long as via that route. In a preferred embodiment, the nay be introduced into the subject by any conventional intravenous, intradermal, intramusclar, intramammary, rejtrobulbar, intrapulmonary (e.g., term release); by oral, , or transdermal delivery, or by surgical implantation at a nay consist of a single dose or a plurality of doses over a tinual release of the compositions of the present invention con positions adi linistered or may be solid, such as lyophilized, for reconstitution. present invention comprise an effective amount of the or dispersed in a pharmaceutically acceptable carrier or 'pharmaceutically or pharmacologically acceptable" refer that do not produce adverse, allergic, or other to an animal or a human. As used herein, arrier" includes any and all solvents, dispersion media, ungal agents, isotonic and absorption delaying agents and and agents for pharmaceutically active substances is well as any conventional media or agent is incompatible with therapeutic compositions is contemplated. Supplementary ncorporated into the compositions. In some cases, it will rid polypeptide of the invention and another food-intake-glucose-lowering, or plasma lipid-altering agent, such st analog, a CCK or CCK agonist, or a leptin or leptin agonist analog, in a single composition or solution for er cases, it may be The hybrid polypeptide of the of free base, or pharmacolo surfactant, such as the acid addition salts (formec formed with inorganic acids s such organic acids as acetic, o free carboxyl groups also car sodium, potassium, ammoniun isopropylamine, trimethylami readily prepared by procedure can be prepared in glycerol, li Under ordinary conditions of s prevent the growth of microor In one embodiment, the ph formulated so as to be infusion. Preferably, the hy example, in an isotonic buffer pH of about 3.5 to about 7.4 sodium citrate-citric acid acetate/acetic acid buffers. A be used so that therapeutically bloodstream over many hours The pharmaceutical composi solutions or dispersions and injectable solutions or dispersi fluid to the extent that easy polypeptide of the invention to and must be preserved again bacteria and fungi. The earn example, water, ethanol, polj hydroxypr jpylcellulose. invention may be prepared for administration as solutions ically acceptable salts in water suitably mixed with a Pharmaceutically-acceptable salts include with the free amino groups of the protein) and which are ich as, for example, hydrochloric or phosphoric acids, or alic, tartaric, mandelic, and the like. Salts formed with the be derived from inorganic bases such as, for example, , calcium, or ferric hydroxides, and such organic bases as te, histidine, procaine and the like. Such products are well known to those skilled in the art. Dispersions also uid polyethylene glycols, and mixtures thereof and in oils. :orage and use, these preparations contain a preservative to anisms. suite ble rmaceutical compositions of the present invention are for parenteral administration, e.g., via injection or rid polypeptide is suspended in an aqueous carrier, for solution at a pH of about 3.0 to about 8.0, preferably at a 3.5 to 6.0, or 3.5 to about 5.0. Useful buffers include nd sodium phosphate-phosphoric acid, and sodium orm of repository or "depot" slow release preparation may ffective amounts of the preparation are delivered into the r days following transdermal injection or delivery. st die ons suitable for injectable use include sterile aqueous powders for the extemporaneous preparation of sterile ns. In all cases, the form should be sterile and should be yringability exists. It is also desirable for the hybrid be stable under the conditions of manufacture and storage t the contaminating action of microorganisms, such as r can be a solvent or dispersion medium containing, for 1 (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the proper fluidity can be maintai by the maintenance of the surfactants. The prevention various antibacterial an antifur sorbic acid, thimerosal, and isotonic agents (for example, injectable compositions can b delaying absorption (for exam Sterile injectable solutions ma required amount in the enumerated above, as required are prepared by incorporatin vehicle that contains the basic those enumerated above. In injectable solutions, the drying techniques that yield a ingredient from a previously st Generally, a therapeutically o polypeptides will be determiti diseases, conditions or disorde s Sciences 697-773. See also Peptides: Stability and Stabi Technical Report No. 10, 0.001 ug/kg body weight/day more or less, as a skilled practi more times daily, or less as described herein. It shoulc dosages recited herein. ike), suitable mixtures thereof, and vegetable oils. The ed, for example, by the use of a coating, such as lecithin, size in the case of dispersion and by the use of F the action of microorganisms can be brought about by gal agents, for example, parabens, chlorobutanol, phenol, ie like. In many cases, it will be preferable to include ugars or sodium chloride). Prolonged absorption of the brought about by the use in the compositions of agents e, aluminum monostearate and gelatin). appi opriate prefen ed be prepared by incorporating the active compounds in the solvent with various of the other ingredients followed by filtered sterilization. Generally, dispersions the various sterilized active ingredients into a sterile lispersion medium and the required other ingredients from ic case of sterile powders for the preparation of sterile methods of preparation are vacuum-drying and freeze->owder of the active ingredient plus any additional desired rile-filtered solution thereof. prophylactically effective amount of the present hybrid d by the age, weight, and condition or severity of the of the recipient. See, e.g., Remington's Pharmaceutical 'Wang Sutp and Hanson, Parenteral Formulations of Proteins and zers, Journal of Parenteral Science and Technology, . 42:2S (1988). Typically, a dosage of between about o about 1000 ug/kg body weight/day, may be used, but oner will recognize, may be used. Dosing may be one or frequently , and may be in conjunction with other compositions be noted that the present invention is not limited to the Appropriate dosages may be determining level of metaboli response data. The final dosage considering factors that mod severity of the damage and t weight, sex and diet of the pa and other clinical factors. A regarding appropriate dosage conditions. ascertained through the use of established assays for conditions or disorders in conjunction with relevant dose-regimen will be determined by the attending physician, y the action of drugs, e.g., the drug's specific activity, : responsiveness of the patient, the age, condition, body ent, the severity of any infection, time of administration studies are conducted, further information will emerge ivels and duration of treatment for specific diseases and An effective dose will typical preferably about 10 to 30 ug tc about 1 mg/day, most prefera administered in a single or about 100 ug/kg/dose. The ex skill in the art and is dependen upon the age, weight and co whenever, e.g., suppression of plasma lipid modulation is de; after diagnosis of obesity. Administration may be by intramuscular, oral, nasal, tran administration, may be increas about 5-100 fold. be in the range of about 1 to 30 ng to about 5 mg/day, about 2 mg/day and more preferably about 5 to 100 (ig to y about 5 ng to about 500 ng/day, for a 50 kg patient, divided doses. Preferably, dosages are between about 0.01 to ct dose to be administered may be determined by one of upon the potency of the particular compound, as well as dition of the individual. Administration should begin utrient availability, food intake, weight, blood glucose or red, for example, at the first sign of symptoms or shortly diabetes mellitus, or insulin-resistance syndrome. my route, e.g., injection, preferably subcutaneous or i dermal, etc. Dosages for certain routes, for example oral d to account for decreased bioavailablity, for example, by In one embodiment, where parenterally, the composition i ranging from 1 ng/kg to 100 0.1 mg/kg to about 50 mg/kg bjody out with an initial bolus fo circulating levels of drug prodifc t te pharmaceutical formulation is to be administered formulation so as to deliver a dose of hybrid polypeptide g/kg body weight/day, preferably at doses ranging from weight/day. Parenteral administration may be carried owed by continuous infusion to maintain therapeutic . Those of ordinary skill in the art will readily optimize effective dosages and administration and the clinical condition oft! regimens as determined by good medical practice ; individual patient. The frequency of dosing wil and the routes of administra determined by one of skill in desired dosage. See, e.g., R 1712. Such formulations m release and rate of in vivo cle of administration, a suitable surface areas or organ size, the appropriate treatment dos without undue experimentatio disclosed herein, as well as clinical trials. depend on the pharmacokinetic parameters of the agents ion. The optimal pharmaceutical formulation will be the art depending on the route of administration and the mington's Pharmaceutical Sciences, supra, pages 1435-y influence the physical state, stability, rate of in vivo •ance of the administered agents. Depending on the route lose may be calculated according to body weight, body Further refinement of the calculations necessary to determine is routinely made by those of ordinary skill in the art , especially in light of the dosage information and assays he pharmacokinetic data observed in animals or human It will be appreciated that the invention may be useful in fie subject to be treated may b veterinary purposes, subjects pigs, horses and goats, animals, laboratory animals i * poultry such as chickens, turke In addition, the present i the invention, components for pharmaceutical applicatioi components for To assist in understanding th harmaceutical compositions and treatment methods of the ds of human medicine and veterinary medicine. Thus the a mammal, preferably human or other animal. For nclude for example, farm animals including cows, sheep, companion animals such as dogs and cats, exotic and/or zoo including mice, rats, rabbits, guinea pigs and hamsters; and f$, ducks and geese. invent on contemplates a kit comprising a hybrid polypeptide of suitable for preparing said hybrid polypeptide of the invention and instructions for using said hybrid polypeptide and • pharmaceutical application. present invention, the following Examples are included, his invention should not, of course, be construed as on and such variations of the invention, now known or be within the purview of one skilled in the art are considered to fall within the claimed. ;ope of the invention as described herein and hereinafter EXAMPLES The present invention is limiting examples, which are be construed as limiting the sc present hybrid polypeptides, ar in vitro and/or in vivo. Tho described in these examples r well in the practice of the i practice thereof. However, it light of the present disclosure methods that are disclosed and the spirit and scope of the inve described in more detail with reference to the following non-ffered to more fully illustrate the invention, but are not to thereof. The examples illustrate the preparation of the d the testing of these hybrid polypeptides of the invention e of skill in the art will understand that the techniques present techniques described by the inventors to function indention, and as such constitute preferred modes for the tiould be appreciated that those of skill in the art should in appreciate that many changes can be made in the specific still obtain a like or similar result without departing from tion. Example 1. Preparation of Hvb rid Polvpeptides Peptides of the invention may Technologies, Inc.) using Rinl mmol/g at 0.050-0.100 mmol 0.63 mmol/g (Novabiochem). dissolved at a concentration o (HBTU, l-Hydroxybenzotriaz e assembled on a Symphony peptide synthesizer (Protein amide resin (Novabiochem) with a loading of 0.43-0.49 r a pre-loaded Wang Resin (Fmoc-Tyr(tBu)-Wang resin) Fmoc amino acid (5.0 eq, 0.250-.500 mmol) residues are 0.10 M in l-methyl-2-pyrrolidinone. All other reagents e hydrate and N,N-Diisopropylethylamine ) are prepared e solutions. The Fmoc protected amino acids are then ino acid using, HBTU (2.0 eq, 0.100-0.200 mmol), 1-(1.8 eq, 0.090-0.18 mmol), N,N-Diisopropylethylamine r 2 hours. Following the last amino acid coupling, the 0% (v/v) piperidine in dimethylformamide for 1 hour, etc, the Symphony peptide synthesizer is programmed to c acid (TFA) cleavage of the peptide from resin is carried 1, 3% water and 1% triisopropylsilane for 1 hour. The cleaved peptide is precipitatec and lyophilized. The pellet is reverse phase HPLC using a C 0.1%TFA. using tert-butyl methyl ether, pelleted by centrifugation -dissolved in water (10-15 mL), filtered and purified via 18 column and an acetonitrile/water gradient containing A general procedure for octanoic and stearic acids) is suspended in NMP (5 mL). In dissolved in DMF (5 mL) folio added to the resin and this washed thoroughly with NMP the TFA cleavage for 1 hr. and purification. PEG modification may be cam or a terminal amino group of PEG esters. The resulting PEC phase HPLC and the purity is c Certain exemplary hybrid poly Various modifications to the modifications such as such as substitutions, insertion C-terminally amidated, it is alternatively be in the free acid N-ca^ping the peptides of the invention with fatty acids (e.g., as follows: Peptide on rink amide resin (0.1 mmol) is a separate vial, HBTU (0.3 mmol), HOBt (0.3 mmol) is ved by the addition of DIEA (0.6 mmol). This solution is suspension is shaken for 2 hrs. The solvent is filtered and 5 mLx4) and CH2C12 (20 rnL), dried and is subjected to Th|e yield of the desired peptide is ca. 40 mg after cleavage d out in solution on a free epsilon-amino group of lysine purified peptide using commercially available activated ylated derivatives are purified to homogeneity by reverse nfirmed by LC/MS and MALDI-MS. eptides of the invention are shown below in Table 1-1. mbodied compounds are envisioned, such as chemical glycosyl tion, PEG modifications, etc.; amino acid modifications and deletions, etc. Further, even though represented as understood that the hybrid polypeptides of the invention may orm. Table 1-1: Certain Exemplary Hybrid Compounds of the Invention Example 2. Binding Assays The hybrid polypeptides of th Amylin binding assay: invention to amylin receptors membranes prepared from rat sacrificed by decapitation, saline (PBS). From the bounded laterally by the tracts. This basal forebrain ti regions, is weighed and homog acid, pH adjusted to 7.4 with fresh buffer by centrifugation f resuspended in 20 mM HEPES (PMSF). To measure I25l-amylin binding Jul; 73(7): 1025-9), membranes with 125I -amylin at 12-16 pM i 0.5 mg/ml bovine serum album minutes at 2°C. Incubations arc (Whatman Inc., Clifton, N.J.) in order to reduce nonspecific immediately before filtration ml cold PBS. Filters are remov counting efficiency of 77%. the presence of 10~12 to 10"6 M regression using a 4-parameter San Diego). invention may be tested in a variety of receptor binding methodologies generally known to those skilled in the art. bed below. Evalua ion of the binding of some exemplary compounds of the may be carried out as follows in nuclueus accumbens >rain. Male Sprague-Dawley® rats (200-250) grams are Bijains are removed and place in cold phosphate-buffered vential surface, cuts are made rostral to the hypothalamus, olfactory tracts and extending at a 45° angle medially from these sue, containing the nucleus accumbens and surrounding nized in ice-cold 20 mM HEPES buffer (20 mM HEPES MaOH at 23°C). Membranes are washed three times in r 15 minutes at 48,000 x g. The final membrane pellet is buffer containing 0.2 mM phenylmethylsulfonyl fluoride trat (see, Beaumont K et al. Can J Physiol Pharmacol. 1995 from 4 mg original wet weight of tissue are incubated 20 mM HEPES buffer containing 0.5 mg/ml bacitracin, n, and 0.2 mM PMSF. Solutions are incubated for 60 terminated by filtration through GF/B glass fiber filters are presoaked for 4 hours in 0.3% poylethyleneimine bjmding of radiolabeled peptides. Filters are washed with 5 ml cold PBS, and immediately after filtration with 15 d and radioactivity assessed in a gamma-counter at a Competition curves are generated by measuring binding in iinlabeled test compound and are analyzed by nonlinear ogistic equation (Inplot program; GraphPAD Software, CGRP receptor binding assay: to CGRP receptors are essentia prepared from SK-N-MC cells, NYAcadSci. 1992:657,106-except using 13,500 cpm 1251- Adrenomedullin binding assay: Evaluation of the binding of compounds of the invention y as described for amylin except using membranes mown to express CGRP receptors (Muff, R. et.al., Ann 5). Binding assays are performed as described for amylin CGRP /well or 21.7 pM/well (Amersham). investigated using HUVECs Pharmacol. 1995,289:383-5) AMP using an optimum of 25-: large for HUVEC compared to negative control since they do n Calcitonin receptor binding assdv tha: Binding to the adrenomedullin receptor may be contain the adrenomedullin receptor (Kato J et.al., EurJ wing using CHO cells or T47D cells, Ann N YAcadSci. 1992, 657: 46:246-55), as known in the art the Perkin Elmer AlphaScreen™ assay for cyclic ),000 cells per well. Elevation of cAMP levels is not HO cells. As such, CHO cells may be chosen as a t express the adrenomedullin receptor if desired. : Binding to the calcitonin receptor may be investigated which also express the calcitonin receptor (Muff R. et.al, 106-16 and Kuestner R.E. et. al. Mol Pharmacol. 1994, Leptin binding assay: Two in and receptor activation (see e.g 10657-10662). An alkaline ph Yl receptor binding assay: MC cells that endogenously incubated with 60 pM [125I]-Sciences), and with unlabeled F a 96 well polystyrene plate. Tl itro bioassays are routinely used to assess leptin binding , White, et al, 1997. Proc.Natl. Acad. Sci. U. S. A. 94: sphatase("AP")-leptin ("OB") fusion protein ("AP-OB") ition of leptin binding in the absence or presence of ive control) or peptide, by COS-7 cells transfected with e mouse OB receptor ("OB-RL"). Signal transduction Is cotransfected with AP reporter and OB-RL constructs. SEAP") activity in response to stimulation with mouse by chemiluminescence. Membranes are prepared from confluent cultures of SK-N-etfpresses the neuropeptide Yl receptors. Membranes are human Peptide YY (2200 Ci/mmol, PerkinElmer Life j 'F polypeptide for 60 minutes at ambient temperature in en well contents are harvested onto a 96 well glass fiber plate using a Perkin Elmer pli scintillant and counted on a Pee harvester. Dried glass fiber plates are combined with in Elmer scintillation counter. Y2 receptor binding assay: N BE cells that endogenously e incubated with 30 pM [125l]-Sciences), and with unlabeled a 96 well polystyrene plate. T plate using a Perkin Elmer pi scintillant and counted on a mbranes are prepared from confluent cultures of SK-N->resses the neuropeptide Y2 receptors. Membranes are human Peptide YY (2200 Ci/mmol, PerkinElmer Life PF polypeptide for 60 minutes at ambient temperature in en well contents are harvested onto a 96 well glass fiber harvester. Dried glass fiber plates are combined with Per in Elmer scintillation counter. Y4 receptor binding assay: encoding neuropeptide Y4 gen from confluent cell cultures. Pancreatic Polypeptide (2200 PPF polypeptide for 60 minute Then well contents are harvesi plate harvester. Dried glass fi Perkin Elmer scintillation coun DHO-K.1 cells are transiently transfected with cDNA and then forty-eight hours later membranes are prepared Membranes are incubated with 18 pM [I25I]- human i/mmol, PerkinElmer Life Sciences), and with unlabeled at ambient temperature in a 96 well polystyrene plate, d onto a 96 well glass fiber plate using a Perkin Elmer er plates are combined with scintillant and counted on a r. Y5 receptor binding assay: encoding neuropeptide Y5 geni from confluent cell cultures. M YY (2200 Ci/mmol, PerkinElm 60 minutes at ambient temperatjire harvested onto a 96 well glass glass fiber plates are combi scintillation counter. "HO-K1 cells are transiently transfected with cDNA and then forty-eight hours later membranes are prepared mbranes are incubated with 44 pM [I25I]- human Peptide r Life Sciences), and with unlabeled PPF polypeptide for in a 96 well polystyrene plate. Then well contents are iber plate using a Perkin Elmer plate harvester. Dried ed with scintillant and counted on a Perkin Elmer GLP-1 receptor binding assay measured using a binding disp cell membranes, and the liganc are incubated in 20 mM HEPE GLP-1 receptor binding activity and affinity may be acement assay in which the receptor source is RINmSF is [I2SI]GLP-1. Homogenized RINmSF cell membranes buffer with 40,000 cpm [125I]GLP-1 tracer, and varying concentrations of test co: mixtures are filtered through rinsed with ice-cold phosphat scintillation counter. Binding (GraphPad Software, Inc., San impoun|d for 2 hours at 23° C with constant mixing. Reaction lass filter pads presoaked with 0.3% PEI solution and buffered saline. Bound counts are determined using a iffinities are calculated using GraphPad Prism software )iego, CA). Example 3: Mouse Food Intake Assay The hybrid polypeptides of the m ouse food intake assay and fo (DIO) mice. The experimental Female NIH/Swiss mice (8-24 cycle with lights on at 0600. available ad libitum, except as hrs, 1 day prior to experiment, experimental groups. In a typic At time=0 min, all animals are in an amount ranging from atx pre-weighed amount (10-15g) o 60, and 120 min to determine t! Phystol. 267: R178-R184, 199* the food remaining after the e.g weight of the food provided identified by ANOVA (p Example 4: Body Weight Gain invention may be tested for appetite suppression in the their effect on body weight gain in diet-induced obesity >rotocols for the screens are described below. veeks old) are group housed with a 12:12 hour light:dark Water and a standard pelleted mouse chow diet are oted. Animals are fasted starting at approximately 1500 The morning of the experiment, animals are divided into 1 study, n=4 cages with 3 mice/cage. iven an intraperitoneal injection of vehicle or compound ut 10 nmol/kg to 75 nmol/kg, and immediately given a the standard chow. Food is removed and weighed at 30, e amount of food consumed (Morley, Flood et aI.,Am. J. . Food intake is calculated by subtracting the weight of 30, 60, 120, 180 and/or 240 minute time point from the nitially at time=0. Significant treatment effects were Where a significant difference exists, test means are using Dunnett's test (Prism v. 2.01, GraphPad Software n Fattened C57B1/6 (Diet-induced-obesitv. or DIO) Mice Male C57BL/6 mice (4 weeks kcal as fat) or low fat (LF, 11' each mouse is implanted with id at start of study) are fed high fat (HF, 58% of dietary dietary kcal as fat) chow. After 4 weeks on chow,an osmotic pump (Alzet # 2002) that subcutaneously I delivers a predetermined dose weight and food intake are m Experimental, 44: 645-51, +/- sd of % body weight chan; per treatment group (p Excndin/PYY Hybrids; Exemplary hybrid polypeptide truncated exendins (e.g., exenc terminally truncated PYY spanning hybrid polypeptides generally fragment of an exendin-4 anal from PYY truncations. For incorporated between the pepti Table4-l:Exendin/PYY 1995) f hybrid polypeptide continuously for two weeks. Body asured weekly (Surwit et al, Metabolism—Clinical and . Effects of the test compound are expressed as the mean 5 (i.e., % change from starting weight) of at least 14 mice ANOVA, Dunnett's test, Prism v. 2.01, GraphPad Software of the invention were synthesized using a C-terminally n-4(l-28) or5Ala, 14Leu,25Phe-exendin-4( 1-28)) and an N-the 18-36 to 31-36 regions. As such, the exemplary comprise two modules, wherein the first module is a g and the second module is a peptidic enhancer selected comparison, a p-alanine dipeptide spacers were also e building blocks in several variants (see Table 4-1). Hybrids and Their Effects in the Food Intake Assay (Table Removed) As shown in Table 4-1, certair in the food intake assay, assay and proved to be more Cer ain exemplary compounds of the invention showed efficacy peptides were also tested at 75 nmol/kg in the DIO erf cacious than PYY (Figure 1). (Table Removec) Exendin/Arnylin Hybrids: Further exemplary hybrid poly truncated exendin (1-27), C-2'7Ala-Amylin(l-7), and Amy and 14Gln,1MIIArg-sCT(8-27)) appetite suppression (see Tabl of the parent molecul es (data n Table 4-2: Exendin/ leptides of the invention were prepared from C-terminally irminally truncated amylin peptides (e.g., amylin(l-7), n(33-27)), and optional sCT fragments (e.g., sCT(8-10) Whereas both hybrid polypeptides were very active in 4-2), the onset of action differed from the activity profiles t shown). mvlin Hybrids and Their Effect in the FI Assay Both compounds also showed 2). Exendin/CCK-8 Hybrids: Yet further exemplary hybrid length or C-terminally truncated directly or via a linker, prese Further, certain hybrids were while another hybrid incorpor ting All the prepared hybrid polype] Table 4-3: Exendin/CCK xcellent efficacy when screened in the DIO assay (Figure polypeptides of the invention were prepared from full exendin-4 attached to the N-terminus of CCK-8 either ving the N-terminal amide of the CCK-8. (Table 4-3). repared incorporating the naturally occurring Tyr(SO3), the more stable Phe(CH2SO3) group was prepared, tides were active in inhibiting food intake (Table 4-3). i Hybrids and Their Effect in the Food Intake Assay (Table Removed Exemplary exendin/CCK-8 1 nmol/kg (Figures 3A and 3B rebound effect in all compc diminished in as well as hybrids incorpor exendin and the CCK residues 'brid polypeptides were tested in the DIO assay at 25 , The data shows an initial weight loss, followed by a mds. Interestingly, the rebound effect appears to be hybrids incorporating the more hydrolytically stable Phe(CHzSO3) residue, ting the linker 8-amino-3,6-dioxaoctanoyl between the Amvlin/PYY Hybrid: An Amylin/PYY hybrid polyp of each peptide. In-vivo activ: T eptide was synthesized that contained truncated segmentsin the food intake assay is shown in Table 4-4. ble 4-4: Amvlin/PYY Phvbrid (Table Removed)] ascertain if exemplary hyb parent component peptide intake assay at the minimum results are shown below in parent peptides (Compounds fragments thereof), The data the pooled parent peptides. Ir and functional assays (cyclase not shown). d polypeptides of the invention are more potent than their ho|rmones, exemplary compounds were tested in the food Ticacious dose of the more active parent molecule. The Figjres 4A and 4B, which also compares the effects of pooled 11, and 12 are component peptide hormones, analogs or ndicate that several peptides are at least as equipotent as larallel with the in vivo studies, in vitro receptor binding ctivity) have been performed for all the compounds (date While the present invention embodiments, it is understood been described in terms of preferred examples and that variations and modifications will occur to those skilled in the art. Therefore, equivalent variations which co(ne it is intended that the appended claims cover all such within the scope of the invention as claimed. We Claim: 1. A hybrid polypeptide exhibiting at least one hormonal activity, said hybrid polypeptide comprising a first bio-active peptide hormone module covalently linked to at least one additional bio-active peptide hormone module; wherein the bio-active peptide hormone modules are independently selected from the group consisting of : component peptide hormones, fragments of component peptide hormones that exhibit at least one hormonal activity of the component peptide hormones, analogs and derivatives of component peptide hormones that exhibit at least one hormonal activity of the component peptide hormones, fragments of analogs and derivatives of component peptide hormones that exhibit at least one hormonal activity of the component peptide hormones, and peptidic enhancers; the component peptide hormones are independently selected from at least two of the group consisting of: amylin, adrenomedullin (ADM), calcitonin (CT), calcitonin gene related peptide (CGRP), intermedin, cholecystokinin ("CCK"), leptin, peptide YY (PYY), glucagon-like peptide-1 (GLP-1), glucagon-like peptide 2 (GLP-2), oxyntomodulin (OXM), and exendin-4; the peptidic enhancers are independently selected from the group consisting of: structural motifs of component peptide hormones that impart a desired chemical stability, conformational stability, metabolic stability, receptor interaction, protease inhibition, or other pharmacokinetic characteristic to the hybrid polypeptide, and structural motifs of analogs or derivatives of component peptide hormones that impart a desired chemical stability, conformational stability, metabolic stability, receptor interaction, protease inhibition, or other pharmacokinetic characteristic to the hybrid polypeptide; and at least one of the bio-active peptide hormone modules exhibits at least one hormonal activity of a component peptide hormone; and further wherein: when the at least one bio-active peptide hormone module that exhibits at least one hormonal activity of a component peptide hormone is amylin, a fragment of amylin that exhibits at least one hormonal activity, an analog or derivative of amylin that exhibits at least one hormonal activity, or a fragment of an analog or derivative of amylin that exhibits at least one hormonal activity, and the at least one other bio-active peptide hormone module is CCK, a fragment of CCK that exhibits at least one hormonal activity, an analog or derivative of CCK that exhibits at least one hormonal activity, a fragment of an analog or derivative of CCK that exhibits at least one hormonal activity, CT, a fragment of CT that exhibits at least one hormonal activity, an analog or derivative of CT that exhibits at least one hormonal activity, or a fragment of an analog or derivative of CT that exhibits at least one hormonal activity, then the hybrid polypeptide further comprises at least three bio-active peptide hormone modules selected from at least three different component peptide hormones; and when the at least one bio-active peptide hormone module that exhibits at least one hormonal activity of a component peptide hormone is GLP-1, a fragment of GLP-1 that exhibits at least one hormonal activity, an analog or derivative of GLP-1 that exhibits at least one hormonal activity, or a fragment of an analog or derivative of GLP-1 that exhibits at least one hormonal activity, and the at least one other bio-active peptide hormone module is a peptidic enhancer comprising an exendin fragment, then the hybrid polypeptide further comprises at least three bio-active peptide hormone modules. 2. The hybrid polypeptide as claimed in claim 1, wherein the peptidic enhancers are independently selected from the group consisting of: amylin (32-37), amylin (33-37), amylin (34-37), amylin (35-37), amylin (36-37), amylin (37), ADM (47-52), ADM (48-52), ADM (49- 52), ADM (50-52), ADM (51-52), ADM (52), CT (27-32), CT (27-32), CT (28-32), CT (29- 32), CT (30-32), CT (31-32), CT (32), CGRP (32-37), CGRP (33-37), CGRP (34-37), CGRP (35-37), CGRP (36-37), CGRP (37), intermedin (42-47), intermedin (43-47), intermedin (44- 47), intermedin (45-47), intermedin (46-47), intermedin (47), PYY (25-36), PYY (26-36), PYY (27-36), PYY (28-36), PYY (29-36), PYY (30-36), PYY (31-36), PYY (32-36), PYY (25-35), PYY (26-35), PYY (27-35), PYY (28-35), PYY (29-35), PYY (30-35), PYY (31-35), PYY (32-35), frog GLP-1 (29-37), frog GLP-1 (30-37), frog GLP-2 (24-31), exendin-4 (31-39), exendin-4 (32-39), exendin-4 (33-39), exendin-4 (34-39), exendin-4 (35-39), exendin-4 (36- 39), exendin-4 (37-39), exendin-4 (38-39), exendin-4 (39), and analogs thereof. 3. The hybrid polypeptide as claimed in claim 1, wherein at least one of the first bio-active peptide hormone module or the at least one additional bio-active peptide hormone module is a component peptide hormone or fragment of a component peptide hormone that exhibits at least one hormonal activity of the component peptide hormone. 4. The hybrid polypeptide as claimed in claim 1, wherein at least one of the first bio-active peptide hormone module or the at least one additional bio-active peptide hormone module is an analog or derivative of a component peptide hormone that exhibits at least one hormonal activity or a fragment of an analog or derivative of a component peptide hormone that exhibits at least one hormonal activity of the component peptide hormone. 5. The hybrid polypeptide as claimed in claim 1, wherein at least one of the first bio-active peptide hormone module or the at least one additional bio-active peptide hormone module is peptidic enhancer. 6. The hybrid polypeptide as claimed in claim 1, wherein the component peptide hormones are independently selected from the group consisting of: amylin, calcitonin, CCK, PYY, and exendin-4. 7. The hybrid polypeptide as claimed in claim 1, wherein the at least one bio-active peptide hormone module that exhibits at least one hormonal activity is located at the N-terminal portion of the hybrid polypeptide. 8. The hybrid polypeptide as claimed in claim 7, wherein the at least one bio-active peptide hormone module that exhibits at least one hormonal activity located at the N-terminal portion of the hybrid polypeptide is configured in the C-terminal to N-terminal orientation. 9. The hybrid polypeptide as claimed in claim 8, wherein the N-terminal end of the hybrid polypeptide is amidated. 10. The hybrid polypeptide as claimed in claim 1, wherein the at least one bio-active peptide hormone module that exhibits at least one hormonal activity is located at the C-terminal portion of the hybrid polypeptide. 11. The hybrid polypeptide as claimed in claim 10, wherein the C-terminal end of the hybrid polypeptide is amidated. 12. The hybrid polypeptide as claimed in claim 1, wherein the C-terminal end of one bio-active peptide hormone module is directly attached to the N-terminal end of another bio-active peptide hormone module to form the covalent attachment. 13. The hybrid polypeptide as claimed in claim 1, wherein the bio-active peptide hormone modules are covalently attached using one or more linking groups independently selected from the group consisting of: alkyls; dicarboxylic acids PEGs; amino acids; polyaminoacids; bifunctional linkers; aminocaproyl (Aca), (ß-alanyl, 8-amino-3, 6-dioxaoctanoyl, and Gly-Lys-Arg (GKR). 14. The hybrid polypeptide as claimed in claim 1, wherein the first bio-active peptide hormone module is selected from the group consisting of : exendin-4, a fragment of exendin-4 that exhibits at least one hormonal activity, an exendin-4 analog or derivative that exhibits at least one hormonal activity, and a fragment of an exendin-4 analog that exhibits at least one hormonal activity; and the at least one additional bio-active peptide hormone module is independently selected from the group consisting of : amylin, a fragment of amylin that exhibits at least one hormonal activity, an amylin analog or derivative that exhibits at least one hormonal activity, or a fragment of an amylin analog that exhibits at least one hormonal activity, CCK, a fragment of CCK that exhibits at least one hormonal activity, a CCK analog or derivative that exhibits at least one hormonal activity, a fragment of a CCK analog that exhibits at least one hormonal activity, CT, a fragment of CT that exhibits at least one hormonal activity, a CT analog or derivative that exhibits at least one hormonal activity, a fragment of a CT analog that exhibits at least one hormonal activity, and a peptidic enhancer. 15. The hybrid polypeptide as claimed in claim 14, wherein the first bio-active peptide hormone module is selected from the group consisting of : exendin-4, exendin-4 (1-27), exendin-4 (1-28), 14Leu, 25Phe-exendin-4 (1-28) ; 5Ala, l4Leu, 25Phe-exendin-4 (1-28) and l4Leu-exendin-4 (1-28); and the at least one additional bio-active peptide hormone module is independently selected from the group consisting of: 25,28,29 Pro-h-amylin, amylin (1-7), 2,7 Ala-amylin (1-7), sCT (8-10), sCT (8-27), 14Gln11, 118Arg-sCT (8-27), CCK-8, Phe2CCK-8, amylin (33-37), PYY (25-36), PYY (30-36) and PYY (31-36). 16. The hybrid polypeptide as claimed in claim 14, wherein the hybrid polypeptide comprises at least three bio-active peptide hormone modules. 17. They hybrid polypeptide as claimed in claim 14, wherein the hybrid polypeptide comprises at least four bio-active peptide hormone modules. 18. The hybrid polypeptide as claimed in claim 14, wherein the first bio-active peptide hormone module is located at the C-terminal end of the hybrid polypeptide and the at least one additional bio-active peptide hormone module is located at the N-terminal end of the hybrid polypeptide. 19. The hybrid polypeptide as claimed in claim 14, wherein the first bio-active peptide hormone module is located at the N-terminal end of the hybrid polypeptide and the at least one additional bio-active peptide hormone module is located at the C-terminal end of the hybrid polypeptide. 20. The hybrid polypeptide as claimed in claim 1, wherein the first bio-active peptide hormone module is selected from the group consisting of: amylin, a fragment of amylin that exhibits at least one hormonal activity, an amylin analog or derivative that exhibits at least one hormonal activity, and a fragment of an amylin analog that exhibits at least one hormonal activity; and the at least one additional bio-active peptide hormone module is a peptidic enhancer independently selected from the group consisting of: PYY (25-36), PYY (26-36), PYY (27-36), PYY (28-36), PYY (29-36), PYY (30-36), PYY (31-36), PYY (32-36), PYY (25-35), PYY (26-35), PYY (27-35), PYY (28-35), PYY (29-35), PYY (30-35), PYY (31-35), PYY (32-35), and analogs thereof. 21. A hybrid polypeptide as claimed in claim 1 exhibiting at least one hormonal activity, said hybrid polypeptide comprising a first bio-active peptide hormone module covalently linked to a second bio-active peptide hormone module; wherein: the bio-active peptide hormone modules are independently selected from the group consisting of : component peptide hormones, fragments of component peptide hormones that exhibit at least one hormonal activity of the component peptide hormones, analogs and derivatives of component peptide hormones that exhibit at least one hormonal activity of the component peptide hormones, fragments of analogs and derivatives of component peptide hormones that exhibit at least one hormonal activity of the component peptide hormones, and peptidic enhancers; the component peptide hormones are independently selected from at least two of the group consisting of: amylin, PYY, and exendin-4; the peptidic enhancers are independently selected from the group consisting of : structural motifs of component peptide hormones that impart a desired chemical stability, conformational stability, metabolic stability, receptor interaction, protease inhibition, or other pharmacokinetic characteristic to the hybrid polypeptide, and structural motifs of analogs or derivatives of component peptide hormones that impart a desired chemical stability, conformational stability, metabolic stability, receptor interaction, protease inhibition, or other pharmacokinetic characteristic to the hybrid polypeptide; and wherein at least one of the bio-active peptide hormone modules exhibits at least one hormonal activity of a component peptide hormone. 22. The hybrid polypeptide as claimed in claim 21, wherein the peptidic enhancers are independently selected from the group consisting of amylin (32-37), amylin (33-37), amylin (34-37), amylin (35-37), amylin (36-37), amylin (37), PYY (25-36), PYY (26-36), PYY (27-36), PYY (28-36), PYY (29-36), PYY (30-36), PYY (31-36), PYY (32-36), PYY (25-35), PYY (26-35), PYY (27-35), PYY (28-35), PYY (29-35), PYY (30-35), PYY (31-35), PYY (32-35), exendin-4 (31-39), exendin-4 (32-39), exendin-4 (33-39), exendin-4 (34-39), exendin-4 (35-39), exendin-4 (36-39), exendin-4 (37-39), exendin-4 (38-39), exendin-4 (39), and analogs thereof. 23. The hybrid polypeptide as claimed in claim 21, wherein the first bio-active peptide hormone module is located at the C-terminal end of the hybrid polypeptide. 24. The hybrid polypeptide as claimed in claim 21, wherein the first bio-active peptide hormone module is located at the N-terminal end of the hybrid polypeptide. 25. The hybrid polypeptide as claimed in claim 21, wherein the hybrid polypeptide comprises bio-active peptide hormone module combinations selected from the group consisting of: exendin-4/PYY, PYY/exendin-4, exendin/amylin, amylin/exendin, amylin/PYY, and PYY/amylin bio-active peptide hormone modules.

Documents:

4531-DELNP-2006-Abstract-(26-04-2012).pdf

4531-delnp-2006-abstract.pdf

4531-delnp-2006-Assignment-(10-04-2013).pdf

4531-DELNP-2006-Claims-(21-09-2012).pdf

4531-delnp-2006-Claims-(25-09-2012).pdf

4531-DELNP-2006-Claims-(26-04-2012).pdf

4531-delnp-2006-claims.pdf

4531-delnp-2006-Correspondence Others-(03-05-2012).pdf

4531-delnp-2006-Correspondence Others-(10-04-2013).pdf

4531-DELNP-2006-Correspondence Others-(26-04-2012).pdf

4531-delnp-2006-Correspondence Others-(28-01-2013).pdf

4531-DELNP-2006-Correspondence-Others-(21-09-2012).pdf

4531-delnp-2006-Correspondence-Others-(25-09-2012).pdf

4531-DELNP-2006-Correspondence-Others-(28-07-2009).pdf

4531-delnp-2006-Correspondence-Others-(30-11-2010).pdf

4531-delnp-2006-correspondence-others.pdf

4531-delnp-2006-description (complete).pdf

4531-DELNP-2006-Drawings-(26-04-2012).pdf

4531-delnp-2006-drawings.pdf

4531-DELNP-2006-Form-1-(10-04-2013).pdf

4531-DELNP-2006-Form-1-(26-04-2012).pdf

4531-DELNP-2006-Form-1-(28-01-2013).pdf

4531-delnp-2006-form-1.pdf

4531-delnp-2006-Form-2-(10-04-2013).pdf

4531-DELNP-2006-Form-2-(26-04-2012).pdf

4531-delnp-2006-Form-2-(28-01-2013).pdf

4531-delnp-2006-form-2.pdf

4531-delnp-2006-Form-3-(03-05-2012).pdf

4531-DELNP-2006-Form-3-(28-07-2009).pdf

4531-delnp-2006-Form-3-(30-11-2010).pdf

4531-delnp-2006-form-3.pdf

4531-delnp-2006-form-5.pdf

4531-delnp-2006-GPA-(10-04-2013).pdf

4531-delnp-2006-gpa.pdf

4531-delnp-2006-pct-105.pdf

4531-delnp-2006-pct-210.pdf

4531-delnp-2006-pct-220.pdf

4531-delnp-2006-pct-237.pdf

4531-delnp-2006-pct-301.pdf

4531-delnp-2006-pct-304.pdf

4531-delnp-2006-pct-311.pdf

4531-DELNP-2006-Petition-137-(26-04-2012).pdf