US2016244497A1PendingUtilityA1
Fgf21 mutants and uses thereof
Est. expiryOct 10, 2028(~2.2 yrs left)· nominal 20-yr term from priority
Inventors:Kenneth W. WalkerColin GeggRandy Ira HechtEdward John BelouskiYue-Sheng LiMark Leo MichaelsJing XuMurielle Marie Ellison
A61P 3/10A61P 3/00A61P 3/04A61K 38/00C07K 14/50A61K 47/60A61K 38/18A61K 47/48215
44
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Claims
Abstract
The invention provides nucleic acid molecules encoding FGF21 mutant polypeptides, FGF21 mutant polypeptides, pharmaceutical compositions comprising FGF21 mutant polypeptides, and methods for treating metabolic disorders using such nucleic acids, polypeptides, or pharmaceutical compositions.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . An isolated nucleic acid molecule comprising a nucleotide sequence encoding a polypeptide of SEQ ID NO: 4 having at least one amino acid substitution that is:
(a) a lysine residue at one or more of positions 36, 72, 77, 126 and 175; (b) a cysteine residue at one or more of positions 37, 38, 46, 91, 69, 77, 79, 87, 91, 112, 113, 120, 121, 125, 126, 175, 170, and 179; (c) an arginine residue at one or more of positions 56, 59, 69, and 122; (d) a glycine residue at position 170; (e) a glycine residue at position 171;
and combinations of (a)-(e).
2 . A vector comprising the nucleic acid molecule of claim 1 .
3 . A host cell comprising the vector of claim 2 .
4 . The host cell of claim 3 that is a eukaryotic cell.
5 . The host cell of claim 3 that is a prokaryotic cell.
6 . A process of producing a polypeptide encoded by the vector of claim 2 comprising culturing a host cell comprising the vector of claim 2 under suitable conditions to express the polypeptide, and optionally isolating the polypeptide.
7 . A polypeptide produced by the process of claim 6 .
8 . The polypeptide of claim 7 , further comprising a proline or glycine residue added to the C-terminus of the polypeptide.
9 . An isolated polypeptide comprising the amino acid sequence of SEQ ID NO: 4 having at least one amino acid substitution that is:
(a) a lysine residue at one or more of positions 36, 72, 77, 126 and 175; (b) a cysteine residue at one or more of positions 37, 38, 46, 91, 69, 77, 79, 87, 91, 112, 113, 120, 121, 125, 126, 175, 170, and 179; (c) an arginine residue at one or more of positions 56, 59, 69, and 122; (d) a glycine residue at position 170; (e) a glycine residue at position 171;
and combinations of (a)-(e),
10 . The polypeptide of claim 9 , further comprising a proline or glycine residue added to the C-terminus of the polypeptide.
11 . The isolated polypeptide of claim 9 , wherein the polypeptide is covalently linked to one or more polymers.
12 . The isolated polypeptide of claim 11 , wherein the polypeptide is covalently linked to one polymer.
13 . The isolated polypeptide of claim 12 , wherein the polymer is a water-soluble polymer.
14 . The isolated polypeptide of claim 13 , wherein the water-soluble polymer is polyethylene glycol (PEG), monomethoxy-polyethylene glycol, dextran, cellulose, poly-(N-vinyl pyrrolidone) polyethylene glycol, propylene glycol homopolymers, polypropylene oxide/ethylene oxide co-polymers, polyoxyethylated polyols, or polyvinyl alcohol.
15 . The isolated polypeptide of claim 14 , wherein the water-soluble polymer is PEG.
16 . The isolated polypeptide of claim 11 , wherein the polymer is a branched polymer.
17 . The isolated polypeptide of claim 9 , wherein the polypeptide has a PEG moiety covalently linked to its amino-terminus.
18 . The isolated polypeptide of claim 9 , wherein the polypeptide is covalently linked to two polymers.
19 . The isolated polypeptide of claim 18 , wherein one if the two polymers is a water-soluble polymer.
20 . The isolated polypeptide of claim 19 , wherein the water-soluble polymer is polyethylene glycol (PEG), monomethoxy-polyethylene glycol, dextran, cellulose, poly-(N-vinyl pyrrolidone) polyethylene glycol, propylene glycol homopolymers, polypropylene oxide/ethylene oxide co-polymers, polyoxyethylated polyols, or polyvinyl alcohol.
21 . The isolated polypeptide of claim 20 , wherein the water-soluble polymer is PEG.
22 . The isolated polypeptide of claim 18 , wherein one of the polymers is branched.
23 . The isolated polypeptide of claim 18 , wherein both of the polymers are branched.
24 . The isolated polypeptide of claim 9 , wherein the polypeptide has a PEG moiety covalently linked to its amino-terminus.
25 . A pharmaceutical composition comprising the isolated polypeptide of claim 9 and a pharmaceutically acceptable formulation agent.
26 . The pharmaceutical composition of claim 25 , wherein the pharmaceutically acceptable formulation agent is a carrier, adjuvant, solubilizer, stabilizer, or anti-oxidant.
27 . A method for treating a metabolic disorder comprising administering to a human patient in need thereof the pharmaceutical composition of claim 26 .
28 . The method of claim 27 , wherein the metabolic disorder is diabetes.
29 . The method of claim 27 , wherein the metabolic disorder is obesity.
30 . An isolated nucleic acid encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 4 having at least one amino acid substitution that is:
(a) a lysine residue at one or more of positions 36, 72, 77, 126 and 175; (b) a cysteine residue at one or more of positions 37, 38, 46, 91, 69, 77, 79, 87, 91, 112, 113, 120, 121, 125, 126, 175, 170, and 179; (c) an arginine residue at one or more of positions 56, 59, 69, and 122; (d) a glycine residue at position 170; (e) a glycine residue at position 171;
and combinations of (a)-(e),
and which comprises additions, deletions or further substitutions that make the polypeptide at least 85% identical to SEQ ID NO:4, provided that the at least one amino acid substitution of claim 1 (a)-(e) is not further modified.
31 . A vector comprising the nucleic acid molecule of claim 30 .
32 . A host cell comprising the vector of claim 31 .
33 . The host cell of claim 32 that is a eukaryotic cell.
34 . The host cell of claim 32 that is a prokaryotic cell.
35 . A process of producing a polypeptide encoded by the vector of claim 30 comprising culturing a host cell comprising the vector of claim 30 under suitable conditions to express the polypeptide, and optionally isolating the polypeptide.
36 . A polypeptide produced by the process of claim 35 .
37 . The polypeptide of claim 36 , further comprising a proline or glycine residue added to the C-terminus of the polypeptide.
38 . An isolated polypeptide comprising the amino acid sequence of SEQ ID NO: 4 having at least one amino acid substitution that is:
(a) a lysine residue at one or more of positions 36, 72, 77, 126 and 175; (b) a cysteine residue at one or more of positions 37, 38, 46, 91, 69, 77, 79, 87, 91, 112, 113, 120, 121, 125, 126, 175, 170, and 179; (c) an arginine residue at one or more of positions 56, 59, 69, and 122; (d) a glycine residue at position 170; (e) a glycine residue at position 171;
and combinations of (a)-(e),
and which comprises additions, deletions or further substitutions that make the polypeptide at least 85% identical to SEQ ID NO:4, provided that the at least one amino acid substitution of claim 1 (a)-(e) is not further modified.
39 . The polypeptide of claim 38 , further comprising a proline or glycine residue added to the C-terminus of the polypeptide.
40 . The isolated polypeptide of claim 38 , wherein the polypeptide is covalently linked to one polymer.
41 . The isolated polypeptide of claim 40 , wherein the polymer is a water-soluble polymer.
42 . The isolated polypeptide of claim 41 , wherein the water-soluble polymer is polyethylene glycol (PEG), monomethoxy-polyethylene glycol, dextran, cellulose, poly-(N-vinyl pyrrolidone) polyethylene glycol, propylene glycol homopolymers, polypropylene oxide/ethylene oxide co-polymers, polyoxyethylated polyols, or polyvinyl alcohol.
43 . The isolated polypeptide of claim 42 , wherein the water-soluble polymer is PEG.
44 . The isolated polypeptide of claim 40 , wherein the polymer is branched.
45 . The isolated polypeptide of claim 38 , wherein the polypeptide has a single PEG moiety covalently linked to its amino-terminus.
46 . The isolated polypeptide of claim 38 , wherein the polypeptide is covalently linked to two polymers.
47 . The isolated polypeptide of claim 46 , wherein one if the two polymers is a water-soluble polymer.
48 . The isolated polypeptide of claim 47 , wherein the water-soluble polymer is polyethylene glycol (PEG), monomethoxy-polyethylene glycol, dextran, cellulose, poly-(N-vinyl pyrrolidone) polyethylene glycol, propylene glycol homopolymers, polypropylene oxide/ethylene oxide co-polymers, polyoxyethylated polyols, or polyvinyl alcohol.
49 . The isolated polypeptide of claim 48 , wherein the water-soluble polymer is PEG.
50 . The isolated polypeptide of claim 46 , wherein both of the polymers are water soluble polymers.
51 . The isolated polypeptide of claim 50 , wherein the water-soluble polymers are independently polyethylene glycol (PEG), monomethoxy-polyethylene glycol, dextran, cellulose, poly-(N-vinyl pyrrolidone) polyethylene glycol, propylene glycol homopolymers, polypropylene oxide/ethylene oxide co-polymers, polyoxyethylated polyols, or polyvinyl alcohol and combinations thereof.
52 . The isolated polypeptide of claim 46 , wherein both of the water soluble polymers are PEG.
53 . The isolated polypeptide of claim 46 , wherein one of the polymers is branched.
54 . The isolated polypeptide of claim 46 , wherein both of the polymers are branched.
55 . A pharmaceutical composition comprising the isolated polypeptide of claim 38 and a pharmaceutically acceptable formulation agent.
56 . The pharmaceutical composition of claim 55 , wherein the pharmaceutically acceptable formulation agent is a carrier, adjuvant, solubilizer, stabilizer, or anti-oxidant.
57 . A method for treating a metabolic disorder comprising administering to a human patient in need thereof the pharmaceutical composition of claim 56 .
58 . The method of claim 57 , wherein the metabolic disorder is diabetes.
59 . The method of claim 57 , wherein the metabolic disorder is obesity.
60 . A composition comprising a first polypeptide comprising the amino acid sequence of SEQ ID NO: 4 optionally having at least one amino acid substitution that is:
(a) a lysine residue at one or more of positions 36, 72, 77, 126 and 175; (b) a cysteine residue at one or more of positions 37, 38, 46, 91, 69, 77, 79, 87, 91, 112, 113, 120, 121, 125, 126, 175, 170, and 179; (c) an arginine residue at one or more of positions 56, 59, 69, and 122; (d) a glycine residue at position 170; (e) a glycine residue at position 171;
and combinations of (a)-(e),
joined by a linker to a second polypeptide comprising a polypeptide comprising the amino acid sequence of SEQ ID NO: 4 optionally having at least one amino acid substitution that is:
(a) a lysine residue at one or more of positions 36, 72, 77, 126 and 175;
(b) a cysteine residue at one or more of positions 37, 38, 46, 91, 69, 77, 79, 87, 91, 112, 113, 120, 121, 125, 126, 175, 170, and 179;
(c) an arginine residue at one or more of positions 56, 59, 69, and 122;
(d) a glycine residue at position 170;
(e) a glycine residue at position 171;
and combinations of (a)-(e).
61 . The polypeptide of claim 60 , wherein the first, second or both polypeptides further comprise a proline or glycine residue added to the C-terminus of the polypeptide.
62 . The composition of claim 60 , wherein the linker is a peptide.
63 . The composition of claim 60 , wherein the linker is a water insoluble polymer.
64 . The composition of claim 63 , wherein the water-soluble polymer is polyethylene glycol (PEG), monomethoxy-polyethylene glycol, dextran, cellulose, poly-(N-vinyl pyrrolidone) polyethylene glycol, propylene glycol homopolymers, polypropylene oxide/ethylene oxide co-polymers, polyoxyethylated polyols, or polyvinyl alcohol.
65 . The composition of claim 64 , wherein the water-soluble polymer is PEG.
66 . The composition of claim 60 , wherein the first, second or both polypeptides are further covalently linked to one polymer, in addition to the linker.
67 . The composition of claim 66 , wherein the polymer is a water-soluble polymer.
68 . The composition of claim 67 , wherein the water-soluble polymer is polyethylene glycol (PEG), monomethoxy-polyethylene glycol, dextran, cellulose, poly-(N-vinyl pyrrolidone) polyethylene glycol, propylene glycol homopolymers, polypropylene oxide/ethylene oxide co-polymers, polyoxyethylated polyols, or polyvinyl alcohol.
69 . The composition of claim 68 , wherein the water-soluble polymer is PEG.
70 . The composition of claim 63 , wherein the polymer is branched.
71 . The composition of claim 60 , wherein the composition has a single PEG moiety covalently linked to its amino-terminus.
72 . The composition of claim 60 , wherein the composition is covalently linked to two polymers.
73 . The composition of claim 72 , wherein one if the two polymers is a water-soluble polymer.
74 . The composition of claim 73 , wherein the water-soluble polymer is polyethylene glycol (PEG), monomethoxy-polyethylene glycol, dextran, cellulose, poly-(N-vinyl pyrrolidone) polyethylene glycol, propylene glycol homopolymers, polypropylene oxide/ethylene oxide co-polymers, polyoxyethylated polyols, or polyvinyl alcohol.
75 . The composition of claim 74 , wherein the water-soluble polymer is PEG.
76 . The composition of claim 72 , wherein both of the polymers are water soluble polymers.
77 . The composition of claim 76 , wherein the water-soluble polymers are independently polyethylene glycol (PEG), monomethoxy-polyethylene glycol, dextran, cellulose, poly-(N-vinyl pyrrolidone) polyethylene glycol, propylene glycol homopolymers, polypropylene oxide/ethylene oxide co-polymers, polyoxyethylated polyols, or polyvinyl alcohol and combinations thereof.
78 . The composition of claim 77 , wherein both of the water soluble polymers are PEG.
79 . The isolated polypeptide of claim 72 , wherein one of the polymers is branched.
80 . The isolated polypeptide of 72 wherein both of the polymers are branched.
81 . A pharmaceutical composition comprising the composition of claim 60 and a pharmaceutically acceptable formulation agent.
82 . The pharmaceutical composition of claim 81 , wherein the pharmaceutically acceptable formulation agent is a carrier, adjuvant, solubilizer, stabilizer, or anti-oxidant.
83 . A method for treating a metabolic disorder comprising administering to a human patient in need thereof the pharmaceutical composition of claim 81 .
84 . The method of claim 83 wherein the metabolic disorder is diabetes.
85 . The method of claim 83 , wherein the metabolic disorder is obesity.Join the waitlist — get patent alerts
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