US2011034373A1PendingUtilityA1
Use of an fgf-21 compound and a glp-1 compound for the treatment of obesity
Est. expiryAug 3, 2027(~1 yrs left)· nominal 20-yr term from priority
A61P 3/10A61P 3/04A61P 43/00A61K 38/26A61K 38/1825
61
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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 obesity comprising administering an FGF-21 compound in combination with a GLP-1 compound, wherein the FGF-21 compound is an FGF-21 analog selected from the group consisting of Cys 118 -Cys 134 -FGF-21 (SEQ ID NO: 9), Cys 118 -Cys 134 -Ala 167 -FGF-21 (SEQ ID NO: 10), Cys 21 -Cys 33 -Ala 167 -FGF-21 (SEQ ID NO: 11), Cys 26 -Cys 122 -Ala 167 -FGF-21 (SEQ ID NO: 12), and Cys 118 -Cys 134 -Ala 121 -Ala 167 -FGF-21 (SEQ ID NO: 13).
17 . The method according to claim 16 , wherein the FGF-21 analog is Cys 118 -Cys 134 -Ala 167 -FGF-21 (SEQ ID NO: 10).
18 . The method according to claim 16 , wherein the FGF-21 analog is Cys 118 -Cys 134 -Ala 121 -Ala 167 -FGF-21 (SEQ ID NO: 13).
19 . The method according to claim 16 , wherein the GLP-1 compound is a GLP-1 analog which comprises an amino acid sequence of SEQ ID NO: 14:
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 Xaa Gly Xaa Xaa Xaa Xaa Xaa Xaa Xaa
35 40
Xaa Xaa Xaa
45
wherein
Xaa at position 8 is Gly, Ala, or Val,
Xaa at position 22 is Gly, Glu, Asp, or Lys,
Xaa at position 33 is Val or Ile,
Xaa at position 34 is Lys or Arg,
Xaa at position 36 is Arg or Gly,
Xaa at position 37 is selected from the group consisting of NH 2 , Gly and Pro,
Xaa at position 38 is Ser or absent,
Xaa at position 39 is Ser or absent,
Xaa at position 40 is Gly or absent,
Xaa at position 41 is Ala or absent,
Xaa at position 42 is Pro or absent,
Xaa at position 43 is Pro or absent,
Xaa at position 44 is Pro or absent, and
Xaa at position 45 is Ser or absent.
20 . The method according to claim 19 , wherein the GLP-1 analog comprises the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17).
21 . The method according to claim 19 , wherein the GLP-1 analog comprises the amino acid sequence of Val 8 -Glu 22 -Ile 33 -Lys 34 -Gly 36 -Pro 37 -Ser 38 -Ser 39 -Gly 40 -Ala 41 -Pro 42 -Pro 43 -Pro 44 -Ser 45 -GLP-1 (SEQ ID NO: 19).
22 . The method according to claim 16 , wherein the GLP-1 compound is a GLP-derivative.
23 . The method according to claim 22 , wherein the GLP-1 derivative 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 .
24 . The method according to claim 16 , wherein the GLP-1 compound is a GLP-1 fusion protein.
25 . The method according to claim 24 , wherein the GLP-1 fusion protein comprises a GLP-1 peptide and an Fc portion of an immunoglobulin, wherein the GLP-1 peptide 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;
and wherein the GLP-1 peptide is fused to the Fc portion of an immunoglobulin comprising the 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.
26 . The method according to claim 25 , wherein the GLP-1 fusion protein further comprises a linker, wherein the linker comprises an amino acid sequence selected from the group consisting of SEQ ID NO:6, SEQ ID NO;7, and SEQ ID NO:8.
27 . A method of lowering body weight comprising administering an FGF-21 compound in combination with a GLP-1 compound, wherein the FGF-21 compound is an FGF-21 analog selected from the group consisting of Cys 118 -Cys 134 -FGF-21 (SEQ ID NO: 9), Cys 118 -Cys 134 -Ala 167 -FGF-21 (SEQ ID NO: 10), Cys 21 -Cys 33 -Ala 167 -FGF-21 (SEQ ID NO: 11), Cys 26 -Cys 122 -Ala 167 -FGF-21 (SEQ ID NO: 12), and Cys 118 -Cys 134 -Ala 121 -Ala 167 -FGF-21 (SEQ ID NO: 13).
28 . The method according to claim 27 , wherein the FGF-21 analog is Cys 118 -Cys 134 -Ala 167 -FGF-21 (SEQ ID NO: 10).
29 . The method according to claim 27 , wherein the FGF-21 analog is Cys 118 -Cys 134 -Ala 121 -Ala 167 -FGF-21 (SEQ ID NO: 13).
30 . The method according to claim 27 , wherein the GLP-1 compound is a GLP-1 analog which comprises an amino acid sequence of SEQ ID NO: 14:
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 Xaa Gly Xaa Xaa Xaa Xaa Xaa Xaa Xaa
35 40
Xaa Xaa Xaa
45
wherein
Xaa at position 8 is Gly, Ala, or Val,
Xaa at position 22 is Gly, Glu, Asp, or Lys,
Xaa at position 33 is Val or Ile,
Xaa at position 34 is Lys or Arg,
Xaa at position 36 is Arg or Gly,
Xaa at position 37 is selected from the group consisting of NH 2 , Gly and Pro,
Xaa at position 38 is Ser or absent,
Xaa at position 39 is Ser or absent,
Xaa at position 40 is Gly or absent,
Xaa at position 41 is Ala or absent,
Xaa at position 42 is Pro or absent,
Xaa at position 43 is Pro or absent,
Xaa at position 44 is Pro or absent, and
Xaa at position 45 is Ser or absent.
31 . The method according to claim 30 , wherein the GLP-1 analog comprises the amino acid sequence of Val 8 -Glu 22 -GLP-1 (SEQ ID NO: 17).
32 . The method according to claim 30 , wherein the GLP-1 analog comprises the amino acid sequence of Val 8 -Glu 22 -Ile 33 -Lys 34 -Gly 36 -Pro 37 -Ser 38 -Ser 39 -Gly 40 -Ala 41 -Pro 42 -Pro 43 -Pro 44 -Ser 45 -GLP-1 (SEQ ID NO: 19).
33 . The method according to claim 27 , wherein the GLP-1 compound is a GLP-1 derivative.
34 . The method according to claim 33 , wherein the GLP-1 derivative 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 .
35 . The method according to claim 27 , wherein the GLP-1 compound is a GLP-1 fusion protein.
36 . The method according to claim 35 , wherein the GLP-1 fusion protein comprises a GLP-1 peptide and an Fc portion of an immunoglobulin wherein the GLP-1 peptide 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;
and wherein the GLP-1 peptide is fused to the Fc portion of an immunoglobulin comprising the 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.
37 . The method according to claim 36 , wherein the GLP-1 fusion protein further comprises a linker, wherein the linker comprises an amino acid sequence selected from the group consisting of SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8.Join the waitlist — get patent alerts
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