Glycoproteins having lipid mobilizing properties and therapeutic uses thereof

Abstract

The invention provides formulations and methods for ameliorating symptoms associated with metabolic disorders, such as cachexia, hypoglycemia, obesity, diabetes, and the like by administering Zn-α 2 -glycoproteins or a functional fragment thereof, alone or in combination with additional agents, such as β adrenergin receptor agonists, β adrenergin receptor antagonists, and/or glycemic control agents.

What is claimed is: 
     
         1 . A formulation comprising a zinc-α 2 -glycoprotein (ZAG), a ZAG variant, a modified ZAG, or a functional fragment thereof. 
     
     
         2 . The formulation of  claim 1 , wherein the ZAG is mammalian. 
     
     
         3 . The formulation of  claim 2 , wherein the ZAG is human. 
     
     
         4 . The formulation of  claim 3 , wherein the ZAG consists of the amino acid sequence set forth in SEQ ID NO: 1. 
     
     
         5 . The formulation of  claim 4 , wherein the ZAG is conjugated to a non-protein polymer. 
     
     
         6 . The formulation of  claim 5 , wherein the ZAG is sialylated, PEGylated or modified to increase solubility or stability. 
     
     
         7 . The formulation of  claim 1 , wherein the ZAG is recombinant or synthetic. 
     
     
         8 . The formulation of  claim 1 , wherein the modified ZAG consists of the wild-type ZAG amino acid sequence with one or more mutations to the amino acid sequence selected from deletions, additions or conservative substitutions. 
     
     
         9 . The formulation of  claim 5 , wherein the ZAG is glycosylated. 
     
     
         10 . The formulation of  claim 1 , wherein the formulation comprises at least 5, 10, 25, 50, 100 mg of ZAG. 
     
     
         11 . The formulation of  claim 1 , further comprising one or more agents selected from the group consisting of a β3 agonist and β-adrenergic receptor (β-AR) antagonist. 
     
     
         12 . The formulation of  claim 11 , wherein the β-AR antagonist is selected from the group consisting of a β2-adrenergic receptor (β2-AR) antagonist, a β1-adrenergic receptor (β1-AR) antagonist, and a β3-adrenergic receptor (β3-AR) antagonist. 
     
     
         13 . The formulation of  claim 11 , wherein the β3 agonist is selected from the group consisting of epinephrine (adrenaline), norepinephrine (noradrenaline), isoprotenerol, isoprenaline, propranolol, alprenolol, arotinolol, bucindolol, carazolol, carteolol, clenbuterol, denopamine, fenoterol, nadolol, octopamine, oxyprenolol, pindolol, [(cyano)pindolol], salbuterol, salmeterol, teratolol, tecradine, trimetoquinolol, 3′-iodotrimetoquinolol, 3′,5′-iodotrimetoquinolol, Amibegron, Solabegron, Nebivolol, AD-9677, AJ-9677, AZ-002, CGP-12177, CL-316243, CL-317413, BRL-37344, BRL-35135, BRL-26830, BRL-28410, BRL-33725, BRL-37344, BRL-35113, BMS-194449, BMS-196085, BMS-201620, BMS-210285, BMS-187257, BMS-187413, the CONH2 substitution of SO3H of BMS-187413, the racemates of BMS-181413, CGP-20712A, CGP-12177, CP-114271, CP-331679, CP-331684, CP-209129, FR-165914, FR-149175, ICI-118551, ICI-201651, ICI-198157, ICI-D7114, LY-377604, LY-368842, KTO-7924, LY-362884, LY-750355, LY-749372, LY-79771, LY-104119, L-771047, L-755507, L-749372, L-750355, L-760087, L-766892, L-746646, L-757793, L-770644, L-760081, L-796568, L-748328, L-748337, Ro-16-8714, Ro-40-2148, (−)-RO-363, SB-215691, SB-220648, SB-226552, SB-229432, SB-251023, SB-236923, SB-246982, SR-58894A, SR-58611, SR-58878, SR-59062, SM-11044, SM-350300, ZD-7114, ZD-2079, ZD-9969, ZM-215001, and ZM-215967. 
     
     
         14 . The formulation of  claim 11 , wherein the β-AR antagonist is selected from the group consisting of propranolol, (−)-propranolol, (+)-propranolol, practolol, (−)-practolol, (+)-practolol, CGP-20712A, ICI-118551, (−)-bupranolol, acebutolol, atenolol, betaxolol, bisoprolol, esmolol, nebivolol, metoprolol, acebutolol, carteolol, penbutolol, pindolol, carvedilol, labetalol, levobunolol, metipranolol, nadolol, sotalol, and timolol. 
     
     
         15 . The formulation of  claim 1 , further comprising a glycemic reducing agent selected from insulin, glucagon-like peptide-1 (GLP-1), or analogs thereof. 
     
     
         16 . The formulation of  claim 1 , further comprising one or more excipients selected from the group consisting of phosphate, Tris, arginine, glycine, Tween 80, sucrose, trehalose, mannitol, casein proteins, and derivatives thereof. 
     
     
         17 . The formulation of  claim 1 , wherein the ZAG, ZAG variant, modified ZAG, or functional fragment thereof is present as polymeric. 
     
     
         18 . A method for delivering a zinc-α 2 -glycoprotein (ZAG) to a mammalian subject, the method comprising delivering to the subject by oral administration the formulation of  claim 1 . 
     
     
         19 . A method of treating a subject to bring about a reduction in weight loss comprising administering to the subject in need of such treatment a therapeutically effective dosage of an inhibitor of the polypeptide having the sequence as shown in SEQ ID NO: 1 alone or in combination with one or more agents selected from the group consisting of a β adrenergic receptor (β-AR) antagonist and a β3-adrenergic receptor (β3-AR) antagonist. 
     
     
         20 . A method of ameliorating symptoms of diabetes or obesity in a mammalian subject comprising administering to the subject in need of such treatment a therapeutically effective dosage of a formulation of  claim 1  in combination with a glycemic reducing agent selected from insulin, glucagon-like peptide-1 (GLP-1), or analogs thereof in any sequence or simultaneously.