US2014024586A1PendingUtilityA1
Use of an fgf-21 compound and a glp-1 compound for the treatment of obesity
Est. expiryAug 3, 2027(~1.1 yrs left)· nominal 20-yr term from priority
A61P 3/10A61P 43/00A61P 3/04A61K 38/1825A61K 38/26
56
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Claims
Abstract
The present invention provides methods of lowering body weight by administering an FGF-21 compound in combination with a GLP- 1 compound. In addition, the present invention also provides methods to treat obesity by administering an FGF- 21 compound in combination with a GLP- 1 compound. The present invention also discloses combinations useful in the methods of the present invention.
Claims
exact text as granted — not AI-modified1 - 15 . (canceled)
16 . A method of treating diabetes comprising administering an FGF-21 compound in combination with a GLP-1 compound, wherein the GLP-1 compound comprises an amino acid sequence of SEQ ID NO: 20:
His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser
10 15
Tyr Leu Glu Xaa Gln Ala Ala Lys Glu Phe Ile Ala
20 25 30
Trp Leu Xaa Lys Gly Gly Pro Ser Ser Gly Ala Pro
35 40
Pro Pro Cys Xaa
45
wherein
Xaa at position 8 is: D-Ala, Gly, Val, Leu, Ile, Ser, or Thr,
Xaa at position 22 is: Gly, Glu, Asp, or Lys;
Xaa at position 33 is: Val or Ile
Xaa at position 46 is: Cys or Cys-NH 2
and wherein one PEG molecule is covalently attached to Cys 45 and one PEG molecule is covalently attached to Cys 46 or Cys 46 -NH 2 .
17 . A method of treating diabetes comprising administering an FGF-21 compound in combination with a GLP-1 compound, wherein the GLP-1 compound is a fusion protein comprising a GLP-1 analog fused via a linker to an FC portion of an immunoglobulin, wherein the GLP-1 analog comprises an amino acid sequence of SEQ ID NO:22:
His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser
10 15
Tyr Leu Glu Glu Gln Ala Ala Lys Glu Phe Ile Ala
20 25 30
Trp Leu Xaa Xaa Gly Gly Xaa
35
wherein
Xaa at position 8 is Gly or Val;
Xaa at position 33 is Val or Lys;
Xaa at position 34 is Lys or Asn;
Xaa at position 37 is Gly, Pro or is absent;
the linker comprises an amino acid sequence of SEQ ID NO:6: Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser,
and the Fc portion comprises an amino acid sequence of SEQ ID NO: 23:
Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys
5 10
Pro Ala Pro Xaa Xaa Xaa Gly Gly Pro Ser Val Phe
15 20
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
25 30 35
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
40 45
Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp
50 55 60
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
65 70
Lys Pro Arg Glu Glu Gln Phe Xaa Ser Thr Tyr Arg
75 80
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
85 90 95
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
100 105
Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
110 115 120
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
125 130
Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn
135 140
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
145 150 155
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
160 165
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
170 175 180
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg
185 190
Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn
195 200
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
205 210 215
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu
220 225
Gly Xaa
230
wherein:
Xaa at position 16 is Pro or Glu;
Xaa at position 17 is Phe, Val, or Ala;
Xaa at position 18 is Leu, Glu, or Ala;
Xaa at position 80 is Asn or Ala; and
Xaa at position 230 is Lys or is absent.
18 . A method of lowering blood glucose levels comprising administering an FGF-21 compound in combination with a GLP-1 compound, wherein the GLP-1 compound comprises an amino acid sequence of SEQ ID NO: 20:
His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser
10 15
Tyr Leu Glu Xaa Gln Ala Ala Lys Glu Phe Ile Ala
20 25 30
Trp Leu Xaa Lys Gly Gly Pro Ser Ser Gly Ala Pro
35 40
Pro Pro Cys Xaa
45
wherein
Xaa at position 8 is: D-Ala, Gly, Val, Leu, Ile, Ser, or Thr,
Xaa at position 22 is: Gly, Glu, Asp, or Lys;
Xaa at position 33 is: Val or Ile
Xaa at position 46 is: Cys or Cys-NH 2
and wherein one PEG molecule is covalently attached to Cys 45 and one PEG molecule is covalently attached to Cys 46 or Cys 46 -NH 2 .
19 . A method of lowering blood glucose levels comprising administering an FGF-21 compound in combination with a GLP-1 compound, wherein the GLP-1 compound is a fusion protein comprising a GLP-1 analog fused via a linker to an FC portion of an immunoglobulin, wherein the GLP-1 analog comprises an amino acid sequence of SEQ ID NO: 22:
His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser
10 15
Tyr Leu Glu Glu Gln Ala Ala Lys Glu Phe Ile Ala
20 25 30
Trp Leu Xaa Xaa Gly Gly Xaa
35
wherein
Xaa at position 8 is Gly or Val;
Xaa at position 33 is Val or Lys;
Xaa at position 34 is Lys or Asn;
Xaa at position 37 is Gly, Pro or is absent;
the linker comprises an amino acid sequence of SEQ ID NO:6: Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser,
and the Fc portion comprises an amino acid sequence of SEQ ID NO:23:
Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys
5 10
Pro Ala Pro Xaa Xaa Xaa Gly Gly Pro Ser Val Phe
15 20
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
25 30 35
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
40 45
Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp
50 55 60
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
65 70
Lys Pro Arg Glu Glu Gln Phe Xaa Ser Thr Tyr Arg
75 80
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
85 90 95
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
100 105
Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
110 115 120
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
125 130
Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn
135 140
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
145 150 155
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
160 165
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
170 175 180
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg
185 190
Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn
195 200
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
205 210 215
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu
220 225
Gly Xaa
230
wherein:
Xaa at position 16 is Pro or Glu;
Xaa at position 17 is Phe, Val, or Ala;
Xaa at position 18 is Leu, Glu, or Ala;
Xaa at position 80 is Asn or Ala; and
Xaa at position 230 is Lys or is absent.
20 . The method according to claim 16 , wherein the FGF21 compound comprises an amino acid sequence comprising a cysteine substitution at positions 21, 26, 33, 118, 119, 121, 122, or 134 of FGF-21 (SEQ ID NO: 2).
21 . The method according to claim 17 , wherein the FGF21 compound comprises an amino acid sequence comprising a cysteine substitution at positions 21, 26, 33, 118, 119, 121, 122, or 134 of FGF-21 (SEQ ID NO: 2).
22 . The method according to claim 18 , wherein the FGF21 compound comprises an amino acid sequence comprising a cysteine substitution at positions 21, 26, 33, 118, 119, 121, 122, or 134 of FGF-21 (SEQ ID NO: 2).
23 . The method according to claim 19 , wherein the FGF21 compound comprises an amino acid sequence comprising a cysteine substitution at positions 21, 26, 33, 118, 119, 121, 122, or 134 of FGF-21 (SEQ ID NO: 2).Cited by (0)
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