Glycoproteins Having Lipid Mobilizing Properties an 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.

1 - 145 . (canceled) 
     
     
         146 . A formulation comprising a zinc-α 2 -glycoprotein (ZAG), a ZAG variant, a modified ZAG, or a functional fragment thereof. 
     
     
         147 . The formulation of  claim 146 , wherein the ZAG is mammalian. 
     
     
         148 . The formulation of  claim 147 , wherein the ZAG is human. 
     
     
         149 . The formulation of  claim 148 , wherein the ZAG consists of the amino acid sequence set forth in SEQ ID NO: 1. 
     
     
         150 . The formulation of  claim 149 , wherein the ZAG is conjugated to a non-protein polymer. 
     
     
         151 . The formulation of  claim 150 , wherein the ZAG is sialylated, PEGylated or modified to increase solubility or stability. 
     
     
         152 . The formulation of  claim 146 , wherein the ZAG is recombinant or synthetic. 
     
     
         153 . The formulation of  claim 146 , 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. 
     
     
         154 . The formulation of  claim 146 , wherein the ZAG further comprises one or more of a leader sequence and a trailing sequence. 
     
     
         155 . The formulation of  claim 150 , wherein the ZAG is glycosylated. 
     
     
         156 . The formulation of  claim 155 , wherein the ZAG is glycosylated as a result of a posttranslational modification. 
     
     
         157 . The formulation of  claim 146 , wherein the functional fragment is generated by proteolysis chemical degradation, or folding-domain-preserving fragmentation. 
     
     
         158 . The formulation of  claim 146 , wherein the formulation comprises at least 5, 10, 25, 50, 100 mg of ZAG. 
     
     
         159 . The formulation of  claim 146 , further comprising a pharmaceutically acceptable carrier. 
     
     
         160 . The formulation of  claim 146 , further comprising one or more agents selected from the group consisting of a β3 agonist and β-adrenergic receptor (β-AR) antagonist. 
     
     
         161 . The formulation of  claim 160 , 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 β-adrenergic receptor (β3-AR) antagonist. 
     
     
         162 . The fonnulation of  claim 160 , 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. 
     
     
         163 . The formulation of  claim 161 , wherein the β3-AR antagonist is SR59230A. 
     
     
         164 . The formulation of  claim 160 , wherein the β3-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. 
     
     
         165 . The formulation of  claim 146 , further comprising a glycemic reducing agent selected from insulin, glucagon-like peptide-1 (GLP-1), or analogs thereof. 
     
     
         166 . The formulation of  claim 146 , wherein the formulation is in the form of a liquid, paste, powder, emulsion, suspension, or solid. 
     
     
         167 . The formulation of  claim 146 , wherein the formulation is in a form suitable for oral administration as a spray, tablet, lyophilized powder, semi-solid gel, sublingual dose, fast-melt dose, buccal dose, liquid dose, lozenge, film, chewed dose, taste-masked dose, or effervescent dose. 
     
     
         168 . The formulation of  claim 146 , wherein the formulation is in a form suitable for intranasal or pulmonary administration, including spray, liquid, paste, emulsion, suspension, lyophilized powder, or semi-solid gel. 
     
     
         169 . The forumlation of  claim 146 , wherein the formulation is in a form suitable for topical administration, including spray, liquid, paste, emulsion, suspension, lyophilized powder, cream, ointment or semi-solid gel. 
     
     
         170 . The formulation of  claim 146 , wherein the formulation is suitable for injection via autoinjectors, pump devices, prefilled syringes, and needle free technologies. 
     
     
         171 . The formulation of  claim 146 , 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. 
     
     
         172 . The formulation of  claim 146 , wherein the ZAG, ZAG variant, modified ZAG, or functional fragment thereof is present as polymeric. 
     
     
         173 . A foodstuff additive or nutritional supplement comprising the formulation of  claim 146 . 
     
     
         174 . A foodstuff or nutritional supplement comprising a consumable carrier in combination with the formulation of  claim 146 . 
     
     
         175 . 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 146 . 
     
     
         176 . A method for increasing a subject's endogenous level of a zinc-α 2 -glycoprotein (ZAG), the method comprising administering to the subject the formulation of  claim 146 . 
     
     
         177 . A method of ameliorating symptoms of cachexia in a subject comprising administering to the subject in need of such treatment a therapeutically effective dosage of an inhibitor of a polypeptide having the sequence as shown in SEQ ID NO: 1, wherein there is amelioration of symptoms associated with cachexia following treatment. 
     
     
         178 . 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 in alone or in combination with one or more agents selected from the group consisting of a βadrenergic receptor (β3-AR) antagonist and a β3-adrenergic receptor (β3-AR) antagonist. 
     
     
         179 . 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 146  in combination with a glycemic reducing agent selected from insulin, glucagon-like peptide-1 (GLP-1), or analogs thereof in any sequence or simultaneously. 
     
     
         180 . A method of monitoring zinc-α 2 -glycoprotein (ZAG) activity in a mammalian subject, comprising:
 a) orally administering the subject the formulation of  claim 146 ; and 
 b) detecting the level of ZAG activity;
 thereby monitoring ZAG activity in the subject.