HEPCIDIN, HEPCIDIN ANTAGONISTS AND METHODS OF USE
First Claim
Patent Images
1. An isolated monoclonal antibody which specifically binds to human hepcidin, wherein said human hepcidin consists of the amino acid sequence set forth in SEQ ID NO:
- 9 and has a conformation comprising four disulfide-bond loops formed between residues 7 and 23, 10 and 13, 11 and 19, and 14 to 22 as located in SEQ ID NO;
9.
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Abstract
The invention relates to purified, correctly folded hepcidin, antibodies that bind hepcidin, and methods of making and using such materials. Also provide are methods of treated hepcidin-related disorders.
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Citations
237 Claims
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1. An isolated monoclonal antibody which specifically binds to human hepcidin, wherein said human hepcidin consists of the amino acid sequence set forth in SEQ ID NO:
- 9 and has a conformation comprising four disulfide-bond loops formed between residues 7 and 23, 10 and 13, 11 and 19, and 14 to 22 as located in SEQ ID NO;
9. - View Dependent Claims (23, 24, 25, 105, 106, 107, 113, 118, 122, 123, 128, 129, 130, 131, 133, 134, 173, 179, 182, 185, 187, 189, 190, 192, 205, 210, 211)
- 9 and has a conformation comprising four disulfide-bond loops formed between residues 7 and 23, 10 and 13, 11 and 19, and 14 to 22 as located in SEQ ID NO;
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2-22. -22. (canceled)
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26-104. -104. (canceled)
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108-112. -112. (canceled)
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114-117. -117. (canceled)
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119-121. -121. (canceled)
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124-127. -127. (canceled)
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132. (canceled)
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135-172. -172. (canceled)
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174-178. -178. (canceled)
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180-181. -181. (canceled)
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183-184. -184. (canceled)
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186. (canceled)
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188. (canceled)
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191. (canceled)
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193. A method of treating a mammal in need thereof comprising administering to said mammal (a) an antibody that binds human hepcidin consisting of SEQ ID NO:
- 9 with a KD of about 10−
7 M or less, and (b) an erythropoiesis stimulator selected from the group consisting of erythropoietin, erythropoietin variants and antibodies that bind erythropoietin.
- 9 with a KD of about 10−
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194-196. -196. (canceled)
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197. A method of treating a mammal that is hypo-responsive to therapy with an erythropoiesis stimulator, comprising administering an antibody that binds human hepcidin consisting of SEQ ID NO:
- 9 with a KD of about 10−
7M or less.
- 9 with a KD of about 10−
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198-204. -204. (canceled)
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206-209. -209. (canceled)
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212-213. -213. (canceled)
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214. A composition of bioactive purified non-urinary, non-mammalian human hepcidin comprising the amino acid sequence set forth in SEQ ID NO:
- 96 wherein at least 75% of the human hepcidin has a C2-C4 disulfide bond, a C5-C7 disulfide bond, a C1-C8 disulfide bond, and a C3-C6 disulfide bond.
- View Dependent Claims (215, 217, 218)
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216. (canceled)
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219. A method of refolding a human hepcidin polypeptide comprising the amino acid sequence set forth in SEQ ID NO:
- 96 to a bioactive form comprising
(a) exposing a human hepcidin polypeptide to a chaotropic agent under conditions that promote denaturing, (b) exposing the product of (a) to an oxidizing agent under conditions that promote renaturing into a properly folded and bioactive form, and (c) recovering a solution comprising the bioactive human hepcidin polypeptide, wherein at least 75% of the human hepcidin polypeptide has at least a C2-C4 disulfide-bond and a C5-C7 disulfide-bond.
- 96 to a bioactive form comprising
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220-227. -227. (canceled)
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228. A hepcidin peptide analog comprising an amino acid sequence that is at least 70% identical to the amino acid sequence set forth in SEQ ID NO:
- 96 that retains all eight cysteines and further retains the C2-C4 disulfide bond.
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229. A hepcidin peptide analog comprising an amino acid sequence that is at least 70% identical to the amino acid sequence set forth in SEQ ID NO:
- 96 that retains all eight cysteines and further retains the C5-C7 disulfide bond.
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230-236. -236. (canceled)
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237. An isolated monoclonal antibody which specifically binds to human hepcidin, wherein said human hepcidin consists of the amino acid sequence set forth in SEQ ID NO:
- 9 and has a conformation comprising at least one disulfide-bond loop formed between residues 10 and 13 and 14 to 22 as located in SEQ ID NO;
9.
- 9 and has a conformation comprising at least one disulfide-bond loop formed between residues 10 and 13 and 14 to 22 as located in SEQ ID NO;
Specification