GIP-BASED MIXED AGONISTS FOR TREATMENT OF METABOLIC DISORDERS AND OBESITY
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Abstract
Glucagon peptides that exhibit GIP agonist activity in addition to glucagon and/or GLP-I activity are provided. Pharmaceutical compositions comprising such glucagon peptides and therapeutic methods of using such peptides are also provided.
128 Citations
166 Claims
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1-33. -33. (canceled)
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34. An analog of glucagon (SEQ ID NO:
- 1) having GIP agonist activity comprising an acyl group, wherein the acyl group is attached to a spacer, wherein;
(i) the spacer is attached to the side chain of the amino acid at position 10 of the analog;
or(ii) the analog comprises an extension of 1 to 21 amino acids C-terminal to the amino acid at position 29 and the spacer is attached to the side chain of an amino acid corresponding to one of positions 37-43 relative to SEQ ID NO;
1;wherein the analog exhibits at least 1% activity of native GIP at the GIP receptor.
- 1) having GIP agonist activity comprising an acyl group, wherein the acyl group is attached to a spacer, wherein;
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35-48. -48. (canceled)
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49. An analog of glucagon (SEQ ID NO:
- 1) having GIP agonist activity, with the following modifications;
(a) an amino acid modification at position 1 that confers GIP agonist activity, (b) a lactam bridge between the side chains of amino acids at positions i and i+4 or between the side chains of amino acids at positions j and j+3, wherein i is 12, 13, 16, 17, 20 or 24, and wherein j is 17, (c) amino acid modifications at one, two or all of positions 27, 28 and 29, and (d) 1-9 further amino acid modifications, wherein the EC50 of the analog for GIP receptor activation is about 10 nM or less, and wherein the EC50 of the analog at the GIP receptor is less than about 50-fold different from its EC50 at the GLP-1 receptor.
- 1) having GIP agonist activity, with the following modifications;
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50-69. -69. (canceled)
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70. An analog of glucagon (SEQ ID NO:
- 1) having GIP agonist activity, comprising;
(a) an amino acid modification at position 1 that confers GIP agonist activity, and (b) an extension of 1 to 21 amino acids C-terminal to the amino acid at position 29, wherein at least one of the amino acids of the extension, corresponding to any of positions 37-43 relative to SEQ ID NO;
1, is acylated or alkylated,wherein the EC50 of the analog for GIP receptor activation is about 10 nM or less, and wherein the EC50 of the analog at the GIP receptor is less than about 50-fold different from its EC50 at the GLP-I receptor. - View Dependent Claims (73)
- 1) having GIP agonist activity, comprising;
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71. (canceled)
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72. (canceled)
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74-99. -99. (canceled)
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100. An analog comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:
- 99-141, 144-164, 166, 192-207, 209-221 and 223 or from the group consisting of SEQ ID NOs;
167-169, 173-178 and 225, or the group consisting of SEQ ID NOs;
5-94.
- 99-141, 144-164, 166, 192-207, 209-221 and 223 or from the group consisting of SEQ ID NOs;
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101-125. -125. (canceled)
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127. (canceled)
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129-134. -134. (canceled)
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136-139. -139. (canceled)
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141. (canceled)
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144. (canceled)
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147. (canceled)
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148. An analog of glucagon (SEQ ID NO:
- 1) having GIP agonist activity, with the following modifications;
(a) an amino acid modification at position 1 that confers GIP agonist activity, (b) one, two, three, or all of the amino acids at positions 16, 20, 21, and 24 of the analog is substituted with an α
,α
-disubstituted amino acid,(c) amino acid modifications at one, two or all of positions 27, 28 and 29, and (d) 1-9 further amino acid modifications, wherein the analog is covalently linked to a hydrophilic moiety, wherein the EC50 of the analog for GIP receptor activation is about 10 nM or less, and wherein the EC50 of the analog at the GIP receptor is less than about 50-fold different from its EC50 at the GLP-1 receptor. - View Dependent Claims (126, 128, 149, 150)
(c) the Met at position 27 is substituted with a large aliphatic amino acid (d) the Asn at position 28 is substituted with a small aliphatic amino acid, and (e) the Thr at position 29 is substituted with a small aliphatic amino acid, (f) or a combination thereof.
- 1) having GIP agonist activity, with the following modifications;
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150. The analog of claim 148, wherein the amino acid at position 1 is Tyr, the amino acid at position 27 is Leu, the amino acid at position 28 is Ala, the amino acid at position 29 is Gly, or a combination thereof.
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151. An analog of glucagon (SEQ ID NO:
- 1) having GIP agonist activity, with the following modifications;
(a) an amino acid modification at position 1 that confers GIP agonist activity, (b) an amino acid substitution of Ser at position 16 with an amino acid of Formula IV; - View Dependent Claims (135, 140, 142, 143, 145, 146, 152, 153, 154, 155, 156, 166)
- 1) having GIP agonist activity, with the following modifications;
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157. An unpegylated analog of glucagon (SEQ ID NO:
- 1) having GIP agonist activity, with the following modifications;
(a) an amino acid modification at position 1 that confers GIP agonist activity, (b) one, two, three, or all of the amino acids at positions 16, 20, 21, and 24 of the analog is substituted with an α
,α
-disubstituted amino acid,(c) amino acid modifications at one, two or all of positions 27, 28 and 29, and (d) 1-9 further amino acid modifications, wherein the EC50 of the analog for GIP receptor activation is about 10 nM or less, and wherein the EC50 of the analog at the GIP receptor is less than about 50-fold different from its EC50 at the GLP-1 receptor. - View Dependent Claims (158, 159)
(c) the Met at position 27 is substituted with a large aliphatic amino acid (d) the Asn at position 28 is substituted with a small aliphatic amino acid, and (e) the Thr at position 29 is substituted with a small aliphatic amino acid, (f) or a combination thereof.
- 1) having GIP agonist activity, with the following modifications;
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159. The analog of claim 157, wherein the amino acid at position 1 is Tyr, the amino acid at position 27 is Leu, the amino acid at position 28 is Ala, the amino acid at position 29 is Gly, or a combination thereof.
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160. An unpegylated analog of glucagon (SEQ ID NO:
- 1) having GIP agonist activity, with the following modifications;
(a) an amino acid modification at position 1 that confers GIP agonist activity, (b) an amino acid substitution of Ser at position 16 with an amino acid of Formula IV; - View Dependent Claims (161, 162, 163, 164, 165)
- 1) having GIP agonist activity, with the following modifications;
Specification